Thienopyrimidine compounds and use thereof

ABSTRACT

The present invention provides a compound represented by the formula:  
                 
 
wherein R 1  is a C 1-4  alkyl; R 2  is (1) a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1′) a halogen, (2′) a hydroxy group, (3′) a C 1-4  alkyl and (4′) a C 1-4  alkoxy, (2) a phenyl which may have a substituent selected from the group consisting of (1′) a halogen, (2′) a C 1-4  alkoxy-C 1-4  alkyl, (3′) a mono-C 1-4  alkyl-carbamoyl-C 1-4  alkyl, (4′) a C 1-4  alkoxy and (5′) a mono-C 1-4  alkylcarbamoyl-C 1-4  alkoxy, or the like; R 3  is a C 1-4  alkyl; R 4  is a C 1-4  alkoxy, or the like; n is an integer of 1 to 4; or a salt thereof, as a thienopyrimidine compound having gonadotropin-releasing hormone antagonistic activity.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of co-pending application Ser. No.10/544,069 filed Jul. 29, 2005, which is the national phase filing ofPCT/JP2004/000741 filed Jan. 28, 2004, the disclosures of which areexpressly incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to thieno[2,3-d]pyrimidine compoundsexhibiting gonadotropin releasing hormone (GnRH) antagonizing activity,their production and use.

BACKGROUND ART

Secretion of anterior pituitary hormones undergoes feedback control byperipheral hormones secreted from target organs of the respectivehormones and by secretion-regulating hormones from the hypothalamus,which is the upper central organ of the anterior lobe of the pituitary(hereinafter, these hormones are collectively called “hypothalamichormones” in this specification). Presently, as hypothalamic hormones,the existence of nine kinds of hormones including, for example,thyrotropin releasing hormone (TRH), and gonadotropin releasing hormone[GnRH, sometimes called as LH-RH (luteinizing hormone releasinghormone)] has been confirmed. These hypothalamic hormones are believedto show their actions via the receptors which are considered to exist inthe anterior lobe of the pituitary, and efforts to find thereceptor-gene expression specific to these hormones, including cases ofhuman, have been made. Accordingly, antagonists or agonists specificallyand selectively acting on these receptors should control the action ofthe hypothalamic hormone and the secretion of anterior pituitaryhormone. As a result, such antagonists or agonists are expected toprevent or treat anterior pituitary hormone dependent diseases.

Known compounds possessing GnRH-antagonizing activity includeGnRH-derived linear peptides (U.S. Pat. No. 5,140,009 and U.S. Pat. No.5,171,835), a cyclic hexapeptide derivative (JP-A-61-191698), a bicyclicpeptide derivative (Journal of Medicinal Chemistry, Vol. 36, pp.3265-3273 (1993)), and so forth. Non-peptide compounds possessingGnRH-antagonizing activity include compounds described in JP-A-8-295693(WO 95/28405), JP-A-9-169768 (WO 96/24597), JP-A-9-169735 (WO 97/14682),JP-A-9-169767 (WO 97/14697), JP-A-11-315079 (WO 99/33831),JP-A-2000-219691 (WO 00/00493), JP-A-2001-278884 (WO 00/56739) andJP-A-2002-30087.

Peptide compounds pose a large number of problems to be resolved withrespect to oral absorbability, dosage form, dose volume, drug stability,sustained action, metabolic stability etc. There is strong demand for anoral GnRH antagonist, especially one based on a non-peptide compound,that has excellent therapeutic effect on hormone-dependent cancers,e.g., prostatic cancer, endometriosis, precocious puberty etc., thatdoes not show transient hypophysial-gonadotropic action (acute action)and that has excellent oral absorbability.

DISCLOSURE OF INVENTION

We, the present inventors, have conducted various investigations, and asa result, have synthesized the following novel compound represented bythe formula [hereinafter sometimes referred to briefly as Compound (I)]:

whereinR¹ is a C₁₋₄ alkyl; R² is (1) a C₁₋₆ alkyl which may have a substituentselected from the group consisting of (1′) a hydroxy group, (2′) a C₁₋₄alkoxy, (3′) a C₁₋₄ alkoxy-carbonyl, (4′) a di-C₁₋₄ alkyl-carbamoyl,(5′) a 5- to 7-membered nitrogen-containing heterocyclic group, (6′) aC₁₋₄ alkyl-carbonyl and (7′) a halogen,(2) a C₃₋₈ cycloalkyl which may have (1′) a hydroxy group or (2′) amono-C₁₋₄ alkyl-carbonylamino, (3) a 5- to 7-memberednitrogen-containing heterocyclic group which may have a substituentselected from the group consisting of (1′) a halogen, (2′) a hydroxygroup, (3′) a C₁₋₄ alkyl and (4′) a C₁₋₄ alkoxy, (4) a phenyl which mayhave a substituent selected from the group consisting of (1′) a halogen,(2′) a C₁₋₄ alkoxy-C₁₋₄ alkyl, (3′) a mono-C₁₋₄ alkyl-carbamoyl-C₁₋₄alkyl, (4′) a C₁₋₄ alkoxy and (5′) a mono-C₁₋₄ alkylcarbamoyl-C₁₋₄alkoxy or (5) a C₁₋₄ alkoxy; R³ is a C₁₋₄ alkyl; R⁴ is (1) a hydrogenatom, (2) a C₁₋₄ alkoxy, (3) a C₆₋₁₀ aryl, (4) a N—C₁₋₄ alkyl-N—C₁₋₄alkylsulfonylamino, (5) a hydroxy group or (6) a 5- to 7-memberednitrogen-containing heterocyclic group which may have a substituentselected from the group consisting of (1′) oxo, (2′) a C₁₋₄ alkyl, (3′)a hydroxy-C₁₋₄ alkyl, (4′) a C₁₋₄ alkoxy-carbonyl, (5′) a mono-C₁₋₄alkyl-carbamoyl and (6′) a C₁₋₄ alkylsulfonyl; n is an integer of 1 to4; provided that when R² is a phenyl which may have a substituent, R⁴ isa 5- to 7-membered nitrogen-containing heterocyclic group which may havea substituent selected from the group consisting of (1) oxo, (2) ahydroxy-C₁₋₄ alkyl, (3) a C₁₋₄ alkoxy-carbonyl, (4) a mono-C₁₋₄alkyl-carbamoyl and (5) a C₁₋₄ alkylsulfonyl; or a salt thereof; whichis characterized by having 3-C₁₋₄ alkoxyureido on the para-position ofits phenyl group at the six position of the thieno[2,3-d]pyrimidineskeleton. And we also have found that Compound (I) has an unexpected,excellent GnRH-antagonizing activity, especially strong antagonisticactivity, based upon the above specific chemical structure, andextremely low toxicity and is therefore satisfactory as a medicinehaving GnRH-antagonizing activity, and developed the present inventionbased on these findings.

Accordingly, the present invention relates to:[1] A compound of the formula:

whereinR¹ is a C₁₋₄ alkyl;R² is(1) a C₁₋₆ alkyl which may have a substituent selected from the groupconsisting of (1′) a hydroxy group, (2′) a C₁₋₄ alkoxy, (3′) a C₁₋₄alkoxy-carbonyl, (4′) a di-C₁₋₄ alkyl-carbamoyl, (5′) a 5- to 7-memberednitrogen-containing heterocyclic group, (6′) a C₁₋₄ alkyl-carbonyl and(7′) a halogen,(2) a C₃₋₈ cycloalkyl which may have (1′) a hydroxy group or (2′) amono-C₁₋₄ alkyl-carbonylamino,(3) a 5- to 7-membered nitrogen-containing heterocyclic group which mayhave a substituent selected from the group consisting of (1′) a halogen,(2′) a hydroxy group, (3′) a C₁₋₄ alkyl and (4′) a C₁₋₄ alkoxy,(4) a phenyl which may have a substituent selected from the groupconsisting of (1′) a halogen, (2′) a C₁₋₄ alkoxy-C₁₋₄ alkyl, (3′) amono-C₁₋₄ alkyl-carbamoyl-C₁₋₄ alkyl, (4′) a C₁₋₄ alkoxy and (5′) amono-C₁₋₄ alkylcarbamoyl-C₁₋₄ alkoxy, or(5) a C₁₋₄ alkoxy;R³ is a C₁₋₄ alkyl;R⁴ is(1) a hydrogen atom,(2) a C₁₋₄ alkoxy,(3) a C₆₋₁₀ aryl,(4) a N—C₁₋₄ alkyl-N—C₁₋₄ alkylsulfonylamino,(5) a hydroxyl group, or(6) a 5- to 7-membered nitrogen-containing heterocyclic group which mayhave a substituent selected from the group consisting of (1′) oxo, (2′)a C₁₋₄ alkyl, (3′) a hydroxy-C₁₋₄ alkyl, (4′) a C₁₋₄ alkoxy-carbonyl,(5′) a mono-C₁₋₄ alkyl-carbamoyl and (6′) a C₁₋₄ alkylsulfonyl;n is an integer of 1 to 4;provided that when R² is a phenyl which may have a substituent, R⁴ is a5- to 7-membered nitrogen-containing heterocyclic group which may have asubstituent selected from the group consisting of (1) oxo, (2) ahydroxy-C₁₋₄ alkyl, (3) a C₁₋₄ alkoxy-carbonyl, (4) a mono-C₁₋₄alkyl-carbamoyl and (5) a C₁₋₄ alkylsulfonyl; or a salt thereof;[2] A compound as defined in [1] above, whereinR² is (1) a C₁₋₄ alkyl which may have a substituent selected from thegroup consisting of (1′) a hydroxy group, (2′) a C₁₋₄ alkoxy, (3′) aC₁₋₄ alkoxy-carbonyl, (4′) a di-C₁₋₄ alkyl-carbamoyl and (5′) a 5 to7-membered nitrogen-containing heterocyclic group,(2) a C₃₋₈ cycloalkyl which may have (1′) a hydroxy group or (2′) amono-C₁₋₄ alkyl-carbonylamino,(3) a 5- to 7-membered nitrogen-containing heterocyclic group which mayhave a substituent selected from the group consisting of (1′) a halogen,(2′) a hydroxy group, (3′) a C₁₋₄ alkyl and (4′) a C₁₋₄ alkoxy,(4) a phenyl which may have a substituent selected from the groupconsisting of (1′) a halogen, (2′) a C₁₋₄ alkoxy-C₁₋₄ alkyl, (3′) amono-C₁₋₄ alkyl-carbamoyl-C₁₋₄ alkyl and (4′) a mono-C₁₋₄alkyl-carbamoyl-C₁₋₄ alkoxy, or(5) a C₁₋₄ alkoxy;R⁴ is(1) a C₁₋₄ alkoxy,(2) a C₆₋₁₀ aryl,(3) a N—C₁₋₄ alkyl-N—C₁₋₄ alkylsulfonylamino or(4) a 5- to 7-membered nitrogen-containing heterocyclic group which mayhave a substituent selected from the group consisting of (1′) oxo, (2′)a hydroxy-C₁₋₄ alkyl, (3′) a C₁₋₄ alkoxy-carbonyl, (4′) a mono-C₁₋₄alkyl-carbamoyl and (5′) a C₁₋₄ alkylsulfonyl;[3] A compound as defined in [1] above, wherein R¹ is methyl;[4] A compound as defined in [1] above, wherein R² is a 5- to 7-memberednitrogen-containing heterocyclic group which may have a substituentselected from the group consisting of (1) a halogen, (2) a hydroxygroup, (3) a C₁₋₄ alkyl and (4) a C₁₋₄ alkoxy;[5] A compound as defined in [1] above, wherein R³ is methyl;[6] A compound as defined in [1] above, wherein R⁴ is a C₁₋₄ alkoxy;[7] A compound as defined in [1] above, wherein n is 2;[8] A compound as defined in [1] above, wherein R³ is methyl, R⁴ is ahydrogen atom and n is 1;[9]N-(4-(1-(2,6-difluorobenzyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-3-(2-pyridinyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,N-(4-(1-(2,6-difluorobenzyl)-5-(((2-ethoxyethyl)(methyl)amino)methyl)-2,4-dioxo-3-(2-pyridinyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyureaorN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxypyridin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a salt thereof;[10]N-(4-(5-(((2-methoxyethyl)methylamino)methyl)-1-(2,6-difluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxo-3-(4-methoxyphenyl)thieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyureaorN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a salt thereof;[11] A prodrug of the compound as defined in [1] above;[12] A pharmaceutical which comprises the compound as defined in [1]above or a prodrug thereof;[13] A pharmaceutical as defined in [12] above, which is agonadotropin-releasing hormone antagonist;[14] A pharmaceutical as defined in [12] above, which is for preventingor treating a sex hormone dependent disease;[16] A pharmaceutical as defined in [12] above, which is for preventingor treating sex hormone-dependent cancer, bone metastasis of sexhormone-dependent cancer, prostatic hypertrophy, hysteromyoma,endometriosis, metrofibroma, precocious puberty, amenorrhea,premenstrual syndrome, dysmenorrhea, multilocular ovary syndrome,polycystic ovary syndrome, acne, alopecia, Alzheimer's disease,infertility, irritable bowel syndrome, benign or malignant tumor whichis hormone independent and LH-RH sensitive or hot flash; reproductionregulator; contraceptive agent; ovulation inducer; or for prevention ofpostoperative recurrence of sex hormone-dependent cancer;[16] A method for antagonizing gonadotropin-releasing hormone, whichcomprises administering an effective amount of the compound as definedin [1] above to a mammal;[17] Use of the compound as defined in [1] above for manufacturing apharmaceutical composition for antagonizing gonadotropin-releasinghormone;[18] A compound of the formula:

whereinR^(a) is (1) a hydrogen atom, (2) an aryl group which may have 1 to 5substituents selected from the group consisting of (i) a halogen, (ii)nitro, (iii) cyano, (iv) amino, (v) a carboxyl group which may beesterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) analkoxy, (ix) an alkylthio, (x) an alkylsulfinyl and (xi) analkylsulfonyl, (3) a cycloalkyl group which may have a substituent or(4) a heterocyclic group which may have a substituent; R^(b) is anitrogen-containing heterocyclic group which may have a substituent;R^(c) is an amino group which may have a substituent; R^(d) is an arylgroup which may have a substituent; p is an integer of 0 to 3; q is aninteger of 0 to 3; or a salt thereof; and so forth.

The definition of each term is described in the following paragraphs.

Examples of the “C₁₋₄ alkyl” include a linear C₁₋₄ alkyl (e.g. methyl,ethyl, propyl, butyl, and the like), a branched C₃₋₄ alkyl (e.g.,isopropyl, isobutyl, sec-butyl, tert-butyl, and the like), and the like.

Examples of the “C₁₋₆ alkyl” include a linear C₁₋₆ alkyl (e.g. methyl,ethyl, propyl, butyl, pentyl, hexyl and the like), a branched C₃₋₆ alkyl(e.g., isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl and thelike), and the like.

Examples of the “C₁₋₄ alkoxy” include a linear C₁₋₄ alkoxy (e.g.methoxy, ethoxy, propoxy, butoxy, and the like), a branched C₃₋₄ alkoxy(e.g., isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like),and the like.

Examples of the “C₁₋₄ alkoxy-carbonyl” include methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, and thelike.

Examples of the “di-C₁₋₄ alkyl-carbamoyl” include dimethylcarbamoyl,diethylcarbamoyl, dipropylcarbamoyl, diisopropylcarbamoyl,N-ethyl-N-methylcarbamoyl, and the like.

Examples of the “5- to 7-membered nitrogen-containing heterocyclicgroup” include pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl,oxazolidin-3-yl, thiazolidin-3-yl, isoxazolidin-2-yl,isothiazolidin-2-yl, imidazolidin-1-yl, imidazolidin-2-yl,imidazolidin-4-yl, pyrazolidin-1-yl, pyrazolidin-3-yl, pyrazolidin-4-yl,pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, imidazol-1-yl, imidazol-2-yl,imidazol-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl,1,2,3-triazol-1-yl, 1,2,5-triazol-1-yl, tetrazol-1-yl, tetrazol-2-yl,tetrazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl,isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl,isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, piperidin-1-yl,piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl,piperazin-2-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl,pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, pyrimidin-2-yl,pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, pyridadin-4-yl, and thelike. Among them, preferable examples are pyrrolidin-1-yl,pyrrolidin-2-yl, imidazol-1-yl, imidazol-2-yl, 1,2,3-triazol-1-yl,1,2,5-triazol-1-yl, tetrazol-1-yl, tetrazol-2-yl, pyridin-2-yl,pyridin-4-yl, and the like.

Examples of the “C₁₋₄ alkyl-carbonyl” include methyl-carbonyl,ethyl-carbonyl, propyl-carbonyl, isopropyl-carbonyl, butyl-carbonyl,isobutyl-carbonyl, sec-butyl-carbonyl, tert-butyl-carbonyl, and thelike.

The “halogen” include fluorine, chlorine, bromine and iodine.

Examples of the “mono-C₁₋₄ alkyl-carbonylamino” includemethylcarbonylamino, ethylcarbonylamino, propylcarbonylamino,isopropylcarbonylamino, butylcarbonylamino, isobutylcarbonylamino,sec-butylcarbonylamino, tert-butylcarbonylamino, and the like.

Examples of the “C₃₋₈ cycloalkyl” include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

The “C₁₋₄ alkoxy-C₁₋₄ alkyl” include methoxymethyl, 1-methoxyethyl,2-methoxyethyl, 1-methoxypropyl, 2-methoxypropyl, 3-methoxypropyl,1-methoxybutyl, 2-methoxybutyl, 3-methoxybutyl, 4-methoxybutyl,1-methoxy-1-methylethyl, 2-methoxy-1-methylethyl,1-methoxy-1-methylpropyl, 2-methoxy-1-methylpropyl,3-methoxy-1-methylpropyl, 1-(methoxymethyl)propyl,1-methoxy-2-methylpropyl, 2-methoxy-2-methylpropyl,3-methoxy-2-methylpropyl, 2-methoxy-1,1-dimethylethyl, ethoxymethyl,2-ethoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, and the like.

Examples of the “mono-C₁₋₄ alkyl-carbamoyl-C₁₋₄ alkyl” includemethylaminocarbonylmethyl, ethylaminocarbonylmethyl,2-methylaminocarbonylethyl, 2-ethylaminocarbonylethyl, and the like.

Examples of the “mono-C₁₋₄ alkyl-carbamoyl-C₁₋₄ alkoxy” includemethylaminocarbonylmethoxy, ethylaminocarbonylmethoxy,2-methylaminocarbonylethoxy, 2-ethylaminocarbonylethoxy, and the like.

Examples of the “C₆₋₁₀ aryl” include phenyl, 1-naphthyl, 2-naphthyl, andthe like.

Examples of the “N—C₁₋₄ alkyl-N—C₁₋₄ alkylsulfonylamino” includeN-methyl-N-methylsulfonylamino, N-ethyl-N-methylsulfonylamino,N-ethylsulfonyl-N-methylamino, N-ethyl-N-ethylsulfonylamino, and thelike.

Examples of the “hydroxy-C₁₋₄ alkyl” include hydroxymethyl,1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl,3-hydroxypropyl, 1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 1-hydroxy-1-methylethyl, 2-hydroxy-1-methylethyl,1-hydroxy-1-methylpropyl, 2-hydroxy-1-methylpropyl,3-hydroxy-1-methylpropyl, 1-(hydroxymethyl)propyl,1-hydroxy-2-methylpropyl, 2-hydroxy-2-methylpropyl,3-hydroxy-2-methylpropyl, 2-hydroxy-1,1-dimethylethyl, and the like.

Examples of the “mono-C₁₋₄ alkyl-carbamoyl” include methylcarbamoyl,ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl,isobutylcarbamoyl, sec-butylcarbamoyl, tert-butylcarbamoyl, and thelike.

Examples of the “C₁₋₄ alkylsulfonyl” include methylsulfonyl,ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl,isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, and the like.

As R¹, methyl and ethyl are preferable, and especially methyl ispreferable.

As R², 5- to 7-membered nitrogen-containing heterocyclic group which mayhave a substituent selected from the group consisting of (1) a halogen,(2) a hydroxy group, (3) a C₁₋₄ alkyl and (4) a C₁₋₄ alkoxy ispreferable. Among them, pyridyl (pyridin-2-yl, pyridin-3-yl,pyridin-4-yl), which may have a substituent selected from the groupconsisting of (1) a halogen, (2) a hydroxy group, (3) a C₁₋₄ alkyl and(4) a C₁₋₄ alkoxy is more preferable. Especially, unsubstitutedpyridin-2-yl is preferable.

As R³, methyl and ethyl are preferable. Especially, methyl ispreferable.

As R⁴, a C₁₋₄ alkoxy is preferable. Especially, methoxy and ethoxy arepreferable.

As n, 1 or 2 is preferable. Especially, 2 is preferable.

Preferable examples of the combination of R³, R⁴ and n, includes thecase that R³ is methyl, R⁴ is a hydrogen atom and n is 1.

Preferable examples of Compound (I) includeN-(4-(1-(2,6-difluorobenzyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-3-(2-pyridinyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,N-(4-(1-(2,6-difluorobenzyl)-5-(((2-ethoxyethyl)(methyl)amino)methyl)-2,4-dioxo-3-(2-pyridinyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyureaorN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxypyridin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea.

Salts of Compound (I) are preferably physiologically acceptable acidaddition salts. Such salts include, for example, salts with inorganicacids (e.g., hydrochloric acid, hydrobromic acid, nitric acid, sulfuricacid, phosphoric acid, etc.), salts with organic acids (e.g., formicacid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid,tartaric acid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,etc.), and the like. When Compound (I) has an acidic group, it may beformed into a physiologically acceptable salt with an inorganic base(e.g., alkali metals and alkaline earth metals such as sodium,potassium, calcium, magnesium, etc.; ammonia, and the like) or anorganic base (e.g., trimethylamine, triethylamine, pyridine, picoline,ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine,N,N′-dibenzylethylenediamine, and the like).

For example, Compound (I) can be produced according to the followingproduction methods. Compounds illustrated in the following reactionschemes include their salts. Examples of the salts include the samesalts as the salts of Compound (I), etc. Compounds (I)-(IV) illustratedin the following reaction schemes may be formed into the acceptablesalts depending on the reaction conditions.

(Production Method 1)

In the above formula, L is a leaving group, and other symbols are thesame as defined above.

Examples of “leaving group” represented by L are a halogen atom, C₁₋₄alkylsulfonyloxy which may have a halogen atom, and the like. Examplesof “C₁₋₄ alkylsulfonyloxy which may have a halogen atom” aremethanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, andthe like.

Compound (II) can be produced in any per se known manner, for example,according to the methods disclosed in JP-A-2001-278884, WO 00/56739 oranalogous methods thereto.

For example, Compound (I) can be produced by reacting Compound (II) anda compound represented by the formula: R⁴—(CH₂)_(n)-L. This reaction ispreferably carried out in the presence of a base.

Examples of “base” are inorganic bases such as sodium carbonate, sodiumhydrogen carbonate, potassium carbonate, potassium hydrogen carbonate,sodium hydroxide, potassium hydroxide, thallium hydroxide, and the like;and organic bases such as triethylamine, diisopropylethylamine,pyridine, and the like.

The amount of the compound represented by the formula: R⁴—(CH₂)_(n)-L inthe reaction of Compound (II) and the compound represented by theformula: R⁴—(CH₂)_(n)-L is about 1 to about 3 moles per 1 mole ofCompound (II). The amount of a base is about 1 to about 3 moles per 1mole of Compound (II).

This reaction is usually carried out in a solvent inert to the reaction.Examples of “solvent” are an ether (e.g., diethyl ether, dioxane,dimethoxyethane, tetrahydrofuran, and the like), an aromatic hydrocarbon(e.g., benzene, toluene, and the like), an amide (e.g.,dimethylformamide, dimethylacetamide, and the like), a halogenatedhydrocarbon (e.g., chloroform, dichloromethane, and the like), and thelike.

The reaction temperature is usually about 0 to about 150° C., preferablyabout 50 to about 80° C. The reaction time is usually about 1 to about24 hours.

(Production Method 2)

In the above formula, R′ is a hydrogen atom or a C₁₋₄ alkyl; R″ is aC₁₋₄ alkyl; and the other symbols are as defined above.

Examples of the C₁₋₄ alkyl represented by R′ and R″ are a linear C₁₋₄alkyl (e.g., methyl, ethyl, propyl, butyl, and the like), a branchedC₃₋₄ alkyl (e.g., isopropyl, isobutyl, sec-butyl, tert-butyl, and thelike), and the like.

Compound (III) can be produced in any per se known manner, for example,by reacting p-nitrophenylacetone with a cyanoacetic ester compound andsulphur [e.g., Chem. Ber., 99, 94-100 (1966)] followed by subjecting theobtained 2-amino-4-methyl-5-(4-nitrophenyl)thiophene to the methodsdisclosed in JP-A-9-169768, WO 96/24597 or analogous methods thereto.

1) When R¹ is hydrogen atom, Compound (I) can be produced by reactingCompound (III) with a compound represented by the formula: R²—NH₂ or asalt thereof in the presence of a condensing agent, to obtain Compound(IV), following by subjecting to cyclization.

Examples of “condensing agent” are WSC(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride), DCC(dicyclohexylcarbodiimide), diethyl cyanophosphate,benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate:PyBOP), and the like.

The amount of “condensing agent” is about 1 to about 3 moles per 1 moleof Compound (III).

This reaction is advantageously carried out in a solvent inert to thereaction.

Examples of the solvent are an alcohol (e.g., ethanol, methanol, and thelike), an aromatic hydrocarbon (e.g., benzene, toluene, and the like),an amide (e.g., dimethylformamide, dimethylacetamide, and the like), ahalogenated hydrocarbon (e.g., chloroform, dichloromethane, and thelike), and so the like.

The reaction temperature is usually about 0 to about 150° C., preferablyabout 0 to 25° C. The reaction time is usually about 1 to about 36hours.

The product as produced in the manner mentioned above may be applied tothe next reaction while it is still crude in the reaction mixture, ormay be isolated from the reaction mixture in any ordinary manner.

Compound (IV) is subjected to cyclization in the presence of a base.

Examples of “base” are inorganic bases such as sodium methoxide, sodiumcarbonate, sodium hydrogen carbonate, potassium carbonate, potassiumhydrogen carbonate, sodium hydroxide, potassium hydroxide, thalliumhydroxide; and organic bases such as triethylamine, pyridine, and thelike; and the like.

The amount of “base” is about 2 to about 20 moles, preferably about 5 toabout 12 mole per 1 mole of Compound (IV).

This reaction is usually carried out in a solvent inert to the reaction.

Examples of the solvent are an alcohol (e.g., ethanol, methanol, and thelike), an aromatic hydrocarbon (e.g., benzene, toluene, and the like),an amide (e.g., dimethylformamide, dimethylacetamide, and the like), ahalogenated hydrocarbon (e.g., chloroform, dichloromethane, and thelike), and the like.

The reaction temperature is usually about 0 to 150° C., preferably roomtemperature (about 15 to 25° C.). The reaction time is usually about 1to 36 hours.

2) When R¹ is an alkyl group, Compound (I) can be produced by reactingCompound (III) with an activated R²—NH₂.

The activated R²—NH₂ can be produced in any per se known manner, forexample, by reacting an organo-aluminum reagent with R²—NH₂ in a solventinert to the reaction.

Examples of “organo-aluminum reagent” are trimethyl aluminum, dimethylaluminum chloride, and the like; and a solution including them, and thelike.

The amount of “organo-aluminum reagent” is about 1 to about 5 moles,preferably about 1 mole per 1 mole of R²—NH₂.

Examples of the solvent are a halogenated hydrocarbon (e.g., chloroform,dichloromethane, and the like).

The reaction temperature is usually about 0 to about 150° C., preferablyabout 0 to 25° C. The reaction time is usually about 1 to about 6 hours.

The cyclization can be carried out by reacting Compound (III) with anactivated R²—NH₂ to obtain Compound (I).

The amount of “Compound (III)” is about 1/5 volume of a mixture ofR²—NH₂ and the organo-aluminum reagent.

This reaction is usually carried out in a solvent inert to the reaction.

Such solvent is the same as those used in the reaction to obtain anactivated R²—NH₂.

The reaction temperature is usually about 0 to about 150° C., preferablyabout 0 to 25° C. The reaction time is usually about 1 to about 48hours.

Compound (I) can also be produced by a known hydrolysis reaction,deprotection reaction, acylation reaction, alkylation reaction,oxidation reaction, cyclization reaction, carbon bond expandingreaction, substituent exchanging reaction, or a combination thereof.

Compound (I) may be isolated and purified by per se known means ofseparation such as recrystallization, distillation and chromatography,and the like.

When Compound (I) is obtained in free form, it can be converted to asalt by per se known methods or methods analogous thereto. When Compound(I) is obtained in salt form, it can be converted to the free form oranother salt by per se known methods or methods analogous thereto.

Compound (I) may be a hydrate or a non-hydrate. The hydrate isexemplified by monohydrate, sesquihydrate and dihydrate.

When Compound (I) is obtained as a mixture of optically activeconfigurations, it can be resolved into the (R)- and (S)-forms by theconventional optical resolution techniques.

Compound (I) can be used as a prodrug. The prodrug of Compound (I) or asalt thereof means a compound which is converted to Compound (I) of thepresent invention under physiological conditions or with a reaction dueto an enzyme, a gastric acid, and the like in the living body, that is,a compound which is converted to Compound (I) of the present inventionwith oxidation, reduction, hydrolysis, and the like according to anenzyme; a compound which is converted to Compound (I) of the presentinvention with gastric acid, etc. The prodrug for Compound (I) may forexample be a compound obtained by subjecting an amino group in Compound(I) to an acylation, alkylation or phosphorylation (e.g., a compoundobtained by subjecting an amino group in Compound (I) or to aneicosanoylation, alanylation, pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylationand tert-butylation, etc.); a compound obtained by subjecting a hydroxygroup in Compound (I) to an acylation, alkylation, phosphorylation orboration (e.g., a compound obtained by subjecting an hydroxy in Compound(I) to an acetylation, palmitoylation, propanoylation, pivaloylation,succinylation, fumarylation, alanylation,dimethylaminomethylcarbonylation, etc.). Any of these compounds can beproduced from Compound (I) by a method known per se.

A prodrug of Compound (I) may also be one which is converted intoCompound (I) under a physiological condition, such as those described in“IYAKUHIN no KAIHATSU (Development of Pharmaceuticals)”, Vol. 7, Designof Molecules, p. 163-198, Published by HIROKAWA SHOTEN (1990).

Compound (I) may be labeled with an isotope (e.g., ³H, ¹⁴C, ³⁵S) and thelike.

In the reaction described above, a starting compound having an aminogroup, a carboxy group or a hydroxy group as its substituent may bepresent as a compound in which a protective group employed ordinarily ina peptide chemistry has been introduced into such a substituent, and anintended compound can be obtained by deprotection if necessary after thereaction.

A protective group for an amino group may for example be an optionallysubstituted C₁₋₆ alkyl-carbonyl (e.g., acetyl, propionyl, and the like),formyl, phenylcarbonyl, a C₁₋₆ alkyloxycarbonyl (e.g., methoxycarbonyl,ethoxycarbonyl, tert-butoxycarbonyl, and the like), phenyloxycarbonyl, aC₇₋₁₄ aralkyloxy-carbonyl (e.g., benzyloxycarbonyl,9-fluorenylmethoxycarbonyl, and the like), trityl, phthaloyl and thelike. Its substituent may for example be a halogen atom (e.g., fluorine,chlorine, bromine and iodine), a C₁₋₆ alkylcarbonyl (e.g., acetyl,propionyl, butyryl, and the like), nitro and the like, and the number ofthe substituents may be 1 to 3.

A protective group for a carboxy may for example be an optionallysubstituted C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, and the like), phenyl, trityl, silyl and the like. Itssubstituent may for example be a halogen atom (e.g., fluorine, chlorine,bromine and iodine), a C₁₋₆ alkylcarbonyl (e.g., acetyl, propionyl,butyryl, and the like), formyl, nitro, and the number of thesubstituents may be 1 to 3.

A protective group for a hydroxy group may for example be an optionallysubstituted C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, and the like), phenyl, a C₇₋₁₀ aralkyl (e.g., benzyl, andthe like), a C₁₋₆ alkylcarbonyl (e.g., acetyl, propionyl, and the like),formyl, phenyloxycarbonyl, a C₇₋₁₀ aralkyloxycarbonyl (e.g.,benzyloxycarbonyl, and the like), tetrahydropyranyl, tetrahydrofuranyl,silyl and the like. Its substituent may for example be a halogen atom(e.g., fluorine, chlorine, bromine and iodine), a C₁₋₆ alkyl, phenyl, aC₇₋₁₁ aralkyl, nitro, and the like, and the number of the substituentsmay be 1 to 4.

The method for introducing and removing the protective group isdemonstrated in accordance with a known method or analogous methodthereof (e.g., the method described in Protective Groups in OrganicChemistry (J. F. W. McOmie et al, Plenum Press)). A deprotection methodmay be a treatment with an acid, base, reduction, UV, hydrazine,phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammoniumfluoride, palladium acetate and the like.

Compound (I) of the present invention or a salt thereof (hereinafteralso referred to as “the compound of the present invention”) possessesexcellent GnRH-antagonizing activity and low toxicity (for example,acute toxicity, chronic toxicity, genetic toxicity, reproductiontoxicity, cardiotoxicity, drug interaction, carcinogenicity). Inaddition, it is excellent in oral absorbability, action sustainability,stability and pharmacokinetics. Also, it is scarcely influenced byplasma ingredients. The compound of the present invention can thereforebe safely used in a mammal (e.g., human, monkey, bovine, horse, dog,cat, rabbit, rat, mouse, etc.) for the preventing and/or treatingdiseases depending on male or female hormones, diseases due to excess ofthese hormones, etc., by suppressing gonadotropin secretion with itsGnRH receptor-antagonizing action to control plasma sex hormoneconcentrations.

For example, the compound of the present invention is useful forpreventing and/or treating sex hormone-dependent cancers (e.g.,prostatic cancer, uterine cancer, breast cancer, pituitary tumor, etc.),bone metastasis of sex hormone-dependent cancer, prostatic hypertrophy,hysteromyoma, endometriosis, metrofibroma, precocious puberty,amenorrhea, premenstrual syndrome, dysmenorrhea, multilocular ovarysyndrome, polycystic ovary syndrome, acne, alopecia, Alzheimer's disease(Alzheimer's disease, senile dementia of Alzheimer type and a mixed typethereof), and the like. The compound of the present invention is alsouseful for the regulation of reproduction in males and females (e.g.,pregnancy regulators, menstruation cycle regulators, etc.). The compoundof the present invention can be also used as a male or femalecontraceptive, or as a female ovulation inducer. Based on its reboundeffect after withdrawal, the compound of the present invention can beused to treat infertility. And the compound of this invention can beused as an agent for preventing and/or treating benign or malignanttumor which is hormone independent and LH-RH sensitive. And the compoundof the present invention can be used as an agent for preventing and/ortreating irritable bowel syndrome and for preventing postoperativerecurrence of sex hormone-dependent cancer (an agent for preventingpostoperative recurrence of prostatic cancer; an agent for preventingpostoperative recurrence of breast cancer or ovarian cancer in thecondition before or after menopause; especially, an agent for preventingpostoperative recurrence of breast cancer or ovarian cancer in thecondition before menopause).

In addition, the compound of the present invention is useful forregulation of animal estrus, improvement of meat quality and promotionof animal growth in the field of animal husbandry. The compound of thepresent invention is also useful as a fish spawning promoter.

The compound of the present invention can be also used to suppress thetransient rise in plasma testosterone concentration (flare phenomenon)observed in administration of a GnRH super-agonist such as leuprorelinacetate. The compound of the present invention can be used incombination with a GnRH super-agonist such as leuprorelin acetate,gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin,deslorelin, meterelin, lecirelin, and the like. Among others, preferredis leuprorelin acetate.

It is also beneficial to use the compound of the present invention inconjunction with at least one member selected from the steroidal ornonsteroidal antiandrogen agent or antiestrogen agent, chemotherapeuticagent, GnRH antagonistic peptide, α-reductase inhibitor, α-receptorinhibitor, aromatase inhibitor, 17β-hydroxysteroid dehydrogenaseinhibitor, adrenal androgen production inhibitor, kinase inhibitor, drugfor hormone therapy, and drug inhibiting cell growth factor or itsreceptor, among others.

The “chemotherapeutic agent” mentioned above includes ifosfamide,adriamycin, peplomycin, cisplatin, cyclophosphamide, 5-FU, UFT,methotrexate, mitomycin C, mitoxantrone, etc.

The “GnRH antagonistic peptide” mentioned above includes non-oral GnRHantagonistic peptides such as cetrorelix, ganirelix, abarelix, etc.

The “adrenal androgen production inhibitor” mentioned above includeslyase (C₁₇, 20-lyase) inhibitors, etc.

The “kinase inhibitor” mentioned above includes tyrosine kinaseinhibitor, etc.

The “drugs for hormone therapy” includes antiestrogens, progesterons(e.g., MPA, etc.), androgens, estrogens and androgen antagonists, amongothers.

The “cell growth factor” may be any substance that promotesproliferation of cells and generally includes peptides with molecularweights not over 20,000 which express the action at low concentrationsthrough binding to receptors. Specifically, there can be mentioned (1)EGF (epidermal growth factor) or substances having substantially thesame activity (e.g., EGF, heregulin (HER2 ligand), etc.), (2) insulin orsubstances having substantially the same activity (e.g., insulin, IGF(insulin-like growth factor)-1, IGF-2, etc.), (3) FGF (fibroblast growthfactor) or substances having substantially the same activity (aFGF,bFGF, KGF (keratinocyte growth factor), HGF (hepatocyte growth factor),FGF-10, etc.), and (4) other growth factors (e.g., CSF (colonystimulating factor), EPO (erythropoietin), IL-2 (interleukin-2), NGF(nerve growth factor), PDGF (platelet-derived growth factor) and TGFβ(transforming growth factor β), etc.), among others.

The “cell growth factor receptor” may be any receptor capable of bindingsaid cell growth factor, including EGF receptor, heregulin receptor(HER2), insulin receptor-1, insulin receptor-2, IGF receptor, FGFreceptor-1, FGF receptor-2, etc.

The drug inhibiting the cell growth factor mentioned above includesherceptin (anti-HER2 receptor antibody), among others.

The drug inhibiting the growth factor mentioned above or its receptorincludes herbimycin, PD153035 [e.g., Science, 265 (5175) p 1093,(1994)], etc.

As a further class of drugs inhibiting the cell growth factor or itsreceptor includes HER2 inhibitors. The HER2 inhibitor may be anysubstance that inhibits the activity of HER2 (e.g., phosphorylatingactivity), thus including an antibody, a low-molecular weight compound(synthetic or natural product), an antisense, an HER2 ligand, heregulin,and any of them as partially modified or mutated in structure. Moreover,it may be a substance which inhibits HER2 activity by inhibiting HER2receptor (e.g. HER2 receptor antibody). The low molecular weightcompound having HER2 inhibiting activity includes, for example, thecompounds described in WO 98/03505, namely1-[3-[4-[2-((E)-2-phenylethenyl)-4-oxazolylmethoxy]phenyl]propyl]-1,2,4-triazoleand the like.

For prostatic hypertrophy, examples of such combination includes thecompound of the present invention in combination with the GnRHsuper-agonist, androgen antagonist, antiestrogen, GnRH antagonisticpeptide, α-reductase inhibitor, α-receptor inhibitor, aromataseinhibitor, 17β-hydroxysteroid dehydrogenase inhibitor, adrenal androgenproduction inhibitor, kinase inhibitor, or the like.

For prostatic cancer, examples of such combination includes the compoundof the present invention in combination with the GnRH super-agonist,androgen antagonist, antiestrogen, chemotherapeutic agent (e.g.,ifosfamide, UFT, adriamycin, peplomycin, cisplatin, etc.), GnRHantagonistic peptide, aromatase inhibitor, 17β-hydroxysteroiddehydrogenase inhibitor, adrenal androgen production inhibitor, kinaseinhibitor, drug for hormone therapy such as estrogenes (e.g., DSB, EMP,etc.), androgen antagonist (e.g., CMA. etc.), drug antagonizing growthfactor or its receptor, and so forth.

For breast cancer, examples of such combination includes the compound ofthe present invention in combination with the GnRH super-agonist,antiestrogen, chemotherapeutic agent (e.g., cyclophosphamide, 5-FU, UFT,methotrexate, adriamycin, mitomycin C, mitoxantrone, etc.), GnRHantagonistic peptide, aromatase inhibitor, adrenal androgen productioninhibitor, kinase inhibitor, drug for hormone therapy such asantiestrogen (e.g., tamoxifen, etc.), progesterons (e.g., MPA, etc.),androgens, estrogens, etc., drug antagonizing growth factor or itsreceptor, or the like.

The administration mode of the compound of the present invention and aconcomitant medicament are not particularly limited, provided that thecompound of the present invention and the concomitant medicament arecombined upon administration. Such an administration mode may forexample be (1) an administration of a single formulation obtained byformulating the compound of the present invention and a concomitantmedicament simultaneously, (2) a simultaneous administration via anidentical route of two formulations obtained by formulating the compoundof the present invention and a concomitant medicament separately, (3) asequential and intermittent administration via an identical route of twoformulations obtained by formulating the compound of the presentinvention and a concomitant medicament separately, (4) a simultaneousadministration via different routes of two formulations obtained byformulating the compound of the present invention and a concomitantmedicament separately, (5) a sequential and intermittent administrationvia different routes of two formulations obtained by formulating thecompound of the present invention and a concomitant medicamentseparately (for example, the compound of the present invention followedby concomitant medicament, or inverse order) and the like.

When the compound of the present invention is used as a preventingand/or treating agent for the above-mentioned diseases or used in thefield of animal husbandry or fishery, it can be administered orally ornon-orally, as formulated with a pharmaceutically acceptable carrier,normally in the form of solid preparations such as tablets, capsules,granules and powders for oral administration, or in the form ofintravenous, subcutaneous, intramuscular or other injections,suppositories or sublingual tablets for non-oral administration. It mayalso be sublingually, subcutaneously, intramuscularly or otherwiseadministered in the form of sustained-release preparations of sublingualtablets, microcapsules, etc. Depending on symptom severity; subject age,sex, weight and sensitivity; duration and intervals of administration;property, dispensing and kind of pharmaceutical preparation; kind ofactive ingredient etc., daily dose is not subject to limitation. For usein the treatment of the above-described sex hormone-dependent cancers(e.g., prostatic cancer, uterine cancer, breast cancer, pituitary tumor,etc.), prostatic hypertrophy, hysteromyoma, endometriosis, precociouspuberty etc., daily dose is normally about 0.01 to 30 mg, preferablyabout 0.02 to 10 mg, and more preferably 0.1 to 10 mg, especiallypreferably 0.1 to 5 mg per kg weight of mammal, normally in 1 to 4divided dosages.

The above doses of the active ingredient (the compound of the presentinvention) for oral administration are applicable to the use of thecompound of the present invention in the field of animal husbandry orfishery. Daily dose is about 0.01 to 30 mg, preferably about 0.1 to 10mg, per kg weight of subject organism, normally in 1 to 3 divideddosages.

In the pharmaceutical composition of the present invention, the amountof Compound (I) is 0.01 to 100% by weight or so of the total weight ofthe composition.

The above pharmaceutically acceptable carriers are various organic orinorganic carrier substances in common use as pharmaceutical materials,including excipients, lubricants, binders and disintegrants for solidpreparations; solvents, dissolution aids, suspending agents, isotonizingagents, buffers and soothing agents for liquid preparations; and thelike. Other pharmaceutical additives such as preservatives,antioxidants, coloring agents and sweetening agents may be used asnecessary.

Preferable examples of excipients include, for example, lactose,sucrose, D-mannitol, starch, crystalline cellulose, light silicicanhydride, and the like. Preferable examples of lubricants include, forexample, magnesium stearate, calcium stearate, talc, colloidal silica,and the like. Preferable examples of binders include, for example,crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, and thelike. Preferable examples of disintegrants include, for example, starch,carboxymethyl cellulose, carboxymethyl cellulose calcium, crosslinkedcarmellose sodium, carboxymethyl starch sodium, and the like. Preferableexamples of solvents include, for example, water for injection, alcohol,propylene glycol, macrogol, sesame oil, corn oil, and the like.Preferable examples of dissolution aids include polyethylene glycol,propylene glycol, D-mannitol, benzyl benzoate, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodiumcitrate, and the like. Preferable examples of suspending agents includesurfactants such as stearyltriethanolamine, sodium lauryl sulfate,laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethoniumchloride, monostearic glycerol, and the like; and hydrophilic polymerssuch as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulosesodium, methyl cellulose, hydroxymethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, and the like. Preferable examples ofisotonizing agents include, for example, sodium chloride, glycerol,D-mannitol, and the like. Preferable examples of buffers include buffersolutions of phosphates, acetates, carbonates, citrates, and the like.Preferable examples of soothing agents include benzyl alcohol, and thelike. Preferable examples of preservatives include paraoxybenzoic acidesters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroaceticacid, sorbic acid, and the like. Preferable examples of antioxidantsinclude sulfites, ascorbic acid, and the like.

By adding suspending agents, dissolution aids, stabilizers, isotonizingagents, preservatives, and the like, the compound of the presentinvention can be prepared as an intravenous, subcutaneous orintramuscular injection by a commonly known method. In such cases, thecompound of the present invention can be freeze-dried as necessary by acommonly known method. In administration to humans, for example, thecompound of the present invention can be safely administered orally ornon-orally as such or as a pharmaceutical composition prepared by mixingit with a pharmacologically acceptable carrier, excipient and diluentselected as appropriate.

Such pharmaceutical compositions include oral preparations (e.g.,powders, granules, capsules, tablets), parenteral preparations [e.g.,injections, drip infusions, external preparations (e.g., nasalpreparations, transdermal preparations, and the like), suppositories(e.g., rectal suppositories, vaginal suppositories, and the like), andthe like].

These preparations can be produced by commonly known methods in commonuse for pharmaceutical making processes.

An injection can be produced by, for example, preparing the compound ofthe present invention as an aqueous injection along with a dispersingagent (e.g., Tween 80 (produced by Atlas Powder Company, USA), HCO 60(produced by Nikko Chemicals Co., Ltd.), polyethylene glycol,carboxymethyl cellulose, sodium alginate, and the like), a preservative(e.g., methyl paraben, propyl paraben, benzyl alcohol, and the like), anisotonizing agent (e.g., sodium chloride, mannitol, sorbitol, glucose,and the like), and the like, or as an oily injection in solution,suspension or emulsion in a vegetable oil such as olive oil, sesame oil,cottonseed oil or corn oil; propylene glycol and the like.

An oral preparation can be produced by formulating the compound of thepresent invention by a compression molding after addition of anexcipient (e.g., lactose, sucrose, starch, and the like), a disintegrant(e.g., starch, calcium carbonate, and the like), a binder (e.g., starch,gum arabic, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropylcellulose, and the like), a lubricant (e.g., talc, magnesium stearate,polyethylene glycol 6000, and the like) and other additives, and, wherenecessary, coating the formulated product for the purpose of tastemasking, enteric dissolution or sustained release by a commonly knownmethod. Coating agents for this purpose include, for example,hydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose,hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, Prulonic F68,cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate,hydroxymethyl cellulose acetate succinate, Eudragit (produced by RohmCompany, Germany; methacrylic acid/acrylic acid copolymer), dyes (e.g.,iron oxide, titanium dioxide), and the like. For an enteric preparation,an intermediate phase may be provided between the enteric phase and thedrug-containing phase for the purpose of separation of the two phases bya commonly known method.

An external preparation can be produced by converting the compound ofthe present invention as a solid, semi-solid or liquid composition by acommonly known method. Such a solid composition is produced by, forexample, powdering the compound of the present invention as such or inmixture with an excipient (e.g., glycol, mannitol, starch,microcrystalline cellulose, and the like), a thickening agent (e.g.,natural rubber, cellulose derivative, acrylic acid polymer, and thelike) and other additives. Such a liquid composition is produced bypreparing the compound of the present invention as an oily or aqueoussuspension in almost the same manner as the injection. The semi-solidcomposition is preferably an aqueous or oily gel, or an ointment. Allthese compositions may contain pH regulators (e.g., carbonic acid,phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, andthe like), preservatives (e.g., paraoxybenzoic acid esters,chlorobutanol, benzalkonium chloride, and the like) and other additives.

A suppository is produced by preparing the compound of the presentinvention as an oily or aqueous solid, semi-solid or liquid compositionby a commonly known method. Useful oily bases for such compositionsinclude glycerides of higher fatty acids (e.g., cacao fat, witepsols(produced by Dynamite Nobel Company, Germany) and the like; medium fattyacids (e.g., MIGLIOL, produced by Dynamite Nobel Company, Germany); andvegetable oils (e.g., sesame oil, soybean oil, cottonseed oil, and thelike). Aqueous bases include, for example, polyethylene glycols andpropylene glycol. Bases for aqueous gels include, for example, naturalrubbers, cellulose derivatives, vinyl polymers and acrylic acidpolymers.

A compound of the formula:

wherein R¹¹ and R¹³ each is a C₁₋₄ alkyl, R¹⁴ is a hydrogen atom or aC₁₋₄ alkoxy and m is an integer of 1 to 4 (hereinafter briefly referredto as Compound (V)) or a salt thereof also has an excellent GnRHantagonizing activity, especially a strong antagonistic activity thoughthe compound falls outside the scope of Compound (I).

Examples of the “C₁₋₄ alkyl” represented by R¹¹ or R¹³ include methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.

Examples of the “C₁₋₄ alkoxy” represented by R¹⁴ include methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,etc.

As R¹¹, methyl is preferable.

As R¹³, methyl is preferable.

As R¹⁴, a hydrogen atom and methoxy are preferable.

Preferable examples of m are 1 and 2.

Preferable examples of Compound (V) areN-(4-(5-(((2-methoxyethyl)methylamino)methyl)-1-(2,6-difluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxo-3-(4-methoxyphenyl)thieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyureaorN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyureaand a salt thereof.

Salts of Compound (V) are preferably physiologically acceptable acidaddition salts. Such salts include, for example, salts with inorganicacids (e.g., hydrochloric acid, hydrobromic acid, nitric acid, sulfuricacid, phosphoric acid), salts with organic acids (e.g., formic acid,acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaricacid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,etc.), and the like. When Compound (V) has an acidic group, it may forma physiologically acceptable salt with an inorganic base (e.g., alkalimetals and alkaline earth metals such as sodium, potassium, calcium andmagnesium, ammonia, and the like) or an organic base (e.g.,trimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,N,N′-dibenzylethylenediamine, and the like).

Compound (V) can be produced by the method described in JP-A-9-169768(WO 96/24597) and JP-A-2001-278884 (WO 00/56739) and its analogousmethod.

Compound (V) may be a hydrate or a non-hydrate. The hydrate isexemplified by monohydrate, sesquihydrate and dihydrate.

Compound (V) can be used as a prodrug. The prodrug means a compoundwhich is converted to Compound (V) by a reaction due to an enzyme, agastric acid, or the like under physiological conditions in the livingbody, that is, a compound which is converted to Compound (V) withoxidation, reduction, hydrolysis, or the like according to an enzyme, ora compound which is converted to Compound (V) with gastric acid, etc.The prodrug for Compound (V) may for example be a compound obtained bysubjecting an amino group in Compound (V) to an acylation, alkylation orphosphorylation (e.g., a compound obtained by subjecting an amino groupin Compound (V) to an eicosanoylation, alanylation,pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylationand tert-butylation, etc.). These compounds can be produced from thecompound of the present invention.

A prodrug of Compound (V) may also be one which is converted intoCompound (V) under a physiological condition, such as those described in“IYAKUHIN no KAIHATSU (Development of Pharmaceuticals)”, Vol. 7, Designof Molecules, p. 163-198, Published by HIROKAWA SHOTEN (1990).

Compound (V) may be labeled with an isotope (e.g., ³H, ¹⁴C, ³⁵S) and thelike.

And the compound represented by the formula:

wherein R^(a) is (1) a hydrogen atom, (2) an aryl group which may have 1to 5 substituent(s) selected from the group consisting of (i) a halogen,(ii) a nitro, (iii) a cyano, (iv) an amino, (v) a carboxyl group whichmay be esterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl,(viii) an alkoxy, (ix) an alkylthio, (x) an alkylsulfinyl and (xi) analkylsulfonyl, (3) a cycloalkyl group which may have a substituent or(4) a heterocyclic group which may have a substituent; R^(b) is anitrogen-containing heterocyclic group which may have a substituent;R^(c) is an amino group which may have a substituent; R^(d) is an arylgroup which may have a substituent; p is an integer of 0 to 3; and q isan integer of 0 to 3 (hereinafter as abbreviated as Compound (A)) or asalt thereof, which contains a part of the Compound (I) of the presentinvention, has an excellent GnRH antagonizing activity, especiallystrong antagonistic activity similar to Compound (I).

The definitions of the substituents of Compound (A) are shown below.

Examples of “aryl” of “aryl group which may have 1 to 5 substituent(s)selected from the group consisting of (i) a halogen, (ii) a nitro, (iii)a cyano, (iv) an amino, (v) a carboxyl group which may be esterified oramidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) an alkoxy, (ix)an alkylthio, (x) an alkylsulfinyl and (xi) an alkylsulfonyl”represented by R^(a) are C₆₋₁₄ aryl such as phenyl, 1-naphthyl,2-naphthyl, anthryl, phenanthryl, acenaphthylenyl, and the like.

Examples of “halogen” of “aryl group which may have 1 to 5substituent(s) selected from the group consisting of (i) a halogen, (ii)a nitro, (iii) a cyano, (iv) an amino, (v) a carboxyl group which may beesterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) analkoxy, (ix) an alkylthio, (x) an alkylsulfinyl and (xi) analkylsulfonyl” represented by R^(a) are fluorine, chlorine, bromine andiodine.

Examples of “carboxyl group which may be esterified or amidated” of“aryl group which may have 1 to 5 substituent(s) selected from the groupconsisting of (i) a halogen, (ii) a nitro, (iii) a cyano, (iv) an amino,(v) a carboxyl group which may be esterified or amidated, (vi) analkylenedioxy, (vii) an alkyl, (viii) an alkoxy, (ix) an alkylthio, (x)an alkylsulfinyl and (xi) an alkylsulfonyl” represented by R^(a) arecarboxyl, a C₁₋₆ alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl,hexyloxycarbonyl, and the like), a C₃₋₆ cycloalkyloxy-carbonyl (e.g.,cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl,cyclohexyloxycarbonyl, and the like), a C₆₋₁₄ aryloxy-carbonyl (e.g.,phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl,anthryloxycarbonyl, phenanthryloxycarbonyl, acenaphthylenyloxycarbonyl,and the like), a C₇₋₁₀ aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, andthe like), carbamoyl, a N-mono-C₁₋₆ alkyl-carbamoyl (e.g.,methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl,butylcarbamoyl, isobutylcarbamoyl, sec-butylcarbamoyl,tert-butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl, and the like), aN-mono-C₃₋₆ cycloalkyl-carbamoyl (e.g., cyclopropylcarbamoyl,cyclobutylcarbamoyl, cyclopentylcarbamoyl, cyclohexylcarbamoyl, and thelike), a N-mono-C₆₋₁₄ aryl-carbamoyl (e.g., phenylcarbamoyl,1-naphthylcarbamoyl, 2-naphthylcarbamoyl, anthrylcarbamoyl,phenanthryloxycarbamoyl, acenaphthylenyloxycarbamoyl, and the like),N-mono-C₇₋₁₀ aralkyl-carbamoyl (e.g., benzylcarbamoyl, and the like),and the like.

Examples of “alkylenedioxy” of “aryl group which may have 1 to 5substituent(s) selected from the group consisting of (i) a halogen, (ii)a nitro, (iii) a cyano, (iv) an amino, (v) a carboxyl group which may beesterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) analkoxy, (ix) an alkylthio, (x) an alkylsulfinyl and (xi) analkylsulfonyl” represented by R^(a) are a C₁₋₆ alkylenedioxy (e.g.,—OCH₂O—, —O(CH₂)₂O—, —O(CH₂)₃O—, —O(CH₂)₄O—, —O(CH₂)₅O—, —O(CH₂)₆O—).

Examples of “alkyl” of “aryl group which may have 1 to 5 substituent(s)selected from the group consisting of (i) a halogen, (ii) a nitro, (iii)a cyano, (iv) an amino, (v) a carboxyl group which may be esterified oramidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) an alkoxy, (ix)an alkylthio, (x) an alkylsulfinyl and (xi) an alkylsulfonyl”represented by R^(a) are a C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, andthe like), and the like.

Examples of “alkoxy” of “aryl group which may have 1 to 5 substituent(s)selected from the group consisting of (i) a halogen, (ii) a nitro, (iii)a cyano, (iv) an amino, (v) a carboxyl group which may be esterified oramidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) an alkoxy, (ix)an alkylthio, (x) an alkylsulfinyl and (xi) an alkylsulfonyl”represented by R^(a) are a C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy,hexyloxy, and the like), and the like.

Examples of “alkylthio” of “aryl group which may have 1 to 5substituent(s) selected from the group consisting of (i) a halogen, (ii)a nitro, (iii) a cyano, (iv) an amino, (v) a carboxyl group which may beesterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) analkoxy, (ix) an alkylthio, (x) an alkylsulfinyl and (xi) analkylsulfonyl” represented by R^(a) are a C₁₋₆ alkylthio (e.g.,methylthio, ethylthio, propylthio, isopropylthio, butylthio,isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio, andthe like), and the like.

Examples of “alkylsulfinyl” of “aryl group which may have 1 to 5substituent(s) selected from the group consisting of (i) a halogen, (ii)a nitro, (iii) a cyano, (iv) an amino, (v) a carboxyl group which may beesterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) analkoxy, (ix) an alkylthio, (x) an alkylsulfinyl and (xi) analkylsulfonyl” represented by R^(a) are a C₁₋₆ alkylsulfinyl (e.g.,methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl,butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl,pentylsulfinyl, hexylsulfinyl, and the like), and the like.

Examples of “alkylsulfonyl” of “aryl group which may have 1 to 5substituent(s) selected from the group consisting of (i) a halogen, (ii)a nitro, (iii) a cyano, (iv) an amino, (v) a carboxyl group which may beesterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) analkoxy, (ix) an alkylthio, (x) an alkylsulfinyl and (xi) analkylsulfonyl” represented by R^(a) are a C₁₋₆ alkylsulfonyl (e.g.,methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl,butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl,pentylsulfonyl, hexylsulfonyl, and the like), and the like.

Examples of “cycloalkyl group” of “cycloalkyl group which may have asubstituent” represented by R^(a) are a C₃₋₆ cycloalkyl (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like), and thelike.

Examples of “heterocyclic group” of “heterocyclic group which may have asubstituent” represented by R^(a) are (1) a 5-membered cyclic groupwhich contains 1 to 4 heteroatom(s) selected from an oxygen atom, asulfur atom, a nitrogen atom and the like in addition to a carbon atom(e.g., 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-(1,2,4-oxadiazolyl),5-(1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3-(1,2,4-thiadiazolyl),5-(1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4-(1,2,3-thiadiazolyl),5-(1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, oxoimidazinyl,dioxotriazinyl, pyrrolidinyl, and the like), (2) a 6-membered cyclicgroup which contains 1 to 4 heteroatom(s) selected from an oxygen atom,a sulfur atom, a nitrogen atom and the like in addition to a carbon atom(e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl, N-oxido-2-pyridyl,N-oxido-3-pyridyl, N-oxido-4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, N-oxido-2-pyrimidinyl, N-oxido-4-pyrimidinyl,N-oxido-5-pyrimidinyl, 2-thiomorpholinyl, 3-thiomorpholinyl,2-morpholinyl, 3-morpholinyl, piperidinyl, pyranyl, thiopyranyl,1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, 2-piperazinyl,3-piperazinyl, triazinyl, oxotriazinyl, 3-pyridazinyl, 4-pyridazinyl,pyrazinyl, N-oxido-3-pyridazinyl, N-oxido-4-pyridazinyl, and the like),and (3) a bicyclic or tricyclic condensed cyclic group which contains 1to 4 heteroatom(s) selected from an oxygen atom, a sulfur atom, anitrogen atom and the like in addition to a carbon atom (e.g.,benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo[1,5-b]pyridazinyl,triazolo[4,5-b]pyridazinyl, benzoimidazolyl, quinolyl, isoquinolyl,cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl,quinolizinyl, 1,8-naphthylidinyl, purinyl, pteridinyl, dibenzofuranyl,carbazolyl, acridinyl, phenanthrydinyl, chromanyl, benzoxazinyl,phenazinyl, phenothiazinyl, phenoxazinyl, and the like).

Examples of “substituent” of “cycloalkyl group which may have asubstituent” and “heterocyclic group which may have a substituent”represented by R^(a) are (i) a C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, andthe like), (ii) a C₂₋₆ alkenyl (e.g., vinyl, allyl, 1-butenyl,2-butenyl, and the like), (iii) a C₂₋₆ alkynyl (e.g., ethynyl,propargyl, 2-butynyl, 5-hexynyl, and the like), (iv) a C₃₋₆ cycloalkyl(e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like),(v) a C₆₋₁₄ aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl, and the like),(vi) a C₇₋₁₄ aralkyl (e.g., benzyl, phenethyl, and the like), (vii) anitro, (viii) a hydroxy, (ix) a mercapto, (x) a cyano, (xi) a carbamoyl,(xii) a carboxyl, (xiii) a C₁₋₆ alkoxy-carbonyl (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl,pentyloxycarbonyl, hexyloxycarbonyl, and the like), (xiv) a sulfo, (xv)a halogen (e.g., fluorine, chlorine, bromine and iodine), (xvi) a C₁₋₆alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like), which mayhave a C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like),(xvii) a C₆₋₁₀ aryloxy (e.g., phenoxy, 1-naphthyloxy, 2-naphthyloxy, andthe like), (xviii) a C₁₋₆ alkylthio (e.g., methylthio, ethylthio,propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio,tert-butylthio, pentylthio, hexylthio, and the like), (xix) a C₆₋₁₀arylthio (e.g., phenylthio, 1-naphthylthio, 2-naphthylthio, and thelike), (xx) a C₁₋₆ alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl,propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl,sec-butylsulfinyl, tert-butylsulfinyl, pentylsulfinyl, hexylsulfinyl,and the like), (xxi) a C₆₋₁₀ arylsulfinyl (e.g., phenylsulfinyl,1-naphthylsulfinyl, 2-naphthylsulfinyl, and the like), (xxii) a C₁₋₆alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl,tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, and the like),(xxiii) a C₆₋₁₀ arylsulfinyl (e.g., phenylsulfonyl, 1-naphthylsulfonyl,2-naphthylsulfonyl, and the like), (xxiv) an amino, (xxv) a C₁₋₆acylamino, (e.g., formylamino, acetylamino, propionylamino,butyrylamino, isobutyrylamino, valerylamino, and the like), (xxvi) amono-C₁₋₆ alkylamino (e.g., methylamino, ethylamino, propylamino,isopropylamino, butylamino, and the like), (xxvii) a di-C₁₋₆ alkylamino(e.g., dimethylamino, diethylamino, dipropylamino, diisopropylamino,dibutylamino, and the like), (xxviii) a C₃₋₆ cycloalkylamino (e.g.,cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino,and the like), (xxix) a C₆₋₁₀ arylamino (e.g., anilino, 1-naphthylamino,2-naphthylamino, and the like), (xxx) a C₁₋₆ acyl (e.g., formyl, acetyl,propionyl, butyryl, isobutyryl, valeryl, and the like), (xxxi) a C₆₋₁₀arylcarbonyl (e.g., benzoyl, 1-naphthylcarbonyl, 2-naphthylcarbonyl, andthe like), (xxxii) a C₁₋₄ alkylenedioxy (e.g., —OCH₂O—, —O(CH₂)₂O—,—O(CH₂)₃O— and —O(CH₂)₄O—), (xxxiii) a 5- or 6-membered heterocyclicgroup which contains 1 to 4 heteroatom(s) selected from an oxygen atom,a sulfur atom, a nitrogen atom and the like in addition to a carbon atom(e.g., 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-(1,2,4-oxadiazolyl),5-(1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3-(1,2,4-thiadiazolyl),5-(1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4-(1,2,3-thiadiazolyl),5-(1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, oxoimidazinyl,dioxotriazinyl, pyrrolidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-thiomorpholinyl,3-thiomorpholinyl, 2-morpholinyl, 3-morpholinyl, piperidinyl, pyranyl,thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, 2-piperazinyl,3-piperazinyl, triazinyl, oxotriazinyl, 3-pyridazinyl, 4-pyridazinyl,pyrazinyl, and the like), (xxxiv) oxo, (xxxv) thioxo, and the like. Thenumber of substituents is 1 to 6, preferably 1 to 3, and thesubstitution position may be any place on which the substitution ispossible.

Examples of “nitrogen-containing heterocyclic group” of“nitrogen-containing heterocyclic group which may have a substituent”represented by R^(b) are a 5- to 7-membered nitrogen-containingheterocyclic group (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl,pyrrolidin-3-yl, oxazolidin-3-yl, thiazolidin-3-yl, isoxazolidin-2-yl,isothiazolidin-2-yl, imidazolidin-1-yl, imidazolidin-2-yl,imidazolidin-4-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, pyrazolidin-4-yl,pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, imidazol-1-yl, imidazol-2-yl,imidazol-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl,1,2,3-triazol-1-yl, 1,2,5-triazol-1-yl, tetrazol-1-yl, tetrazol-2-yl,tetrazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl,isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl,isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, piperidin-1-yl,piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl,piperazin-2-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl,pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, pyrimidin-2-yl,pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, pyridazin-4-yl,1,2,3-triazin-4-yl, 1,2,3-triazin-5-yl, 1,2,4-triazin-3-yl,1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1,3,5-triazin-2-yl,1,2,3,4-tetrazin-5-yl, 1,2,3,5-tetrazin-4-yl, azepan-1-yl, azepan-2-yl,1,2-diazepan-3-yl, 1,2-diazepan-4-yl, 1,2-diazepan-5-yl,1,3-diazepan-2-yl, 1,3-diazepan-4-yl, 1,3-diazepan-5-yl,1,4-diazepan-2-yl, 1,4-diazepan-3-yl, 1,4-diazepan-5-yl,1,2,3-triazepan-4-yl, 1,2,3-triazepan-5-yl, 1,2,4-triazepan-3-yl,1,2,4-triazepan-5-yl, and the like), and the like.

Examples of “substituent” of “nitrogen-containing heterocyclic groupwhich may have a substituent” represented by R^(b) are same number andsame kind as “substituent” of “cycloalkyl group which may have asubstituent” and “heterocyclic group which may have a substituent”represented by R^(a).

Example of “amino group which may have a substituent” represented byR^(c) is a group of the formula: —NR^(e)R^(f) wherein R^(e) is (1) ahydrogen atom, (2) a C₁₋₆ alkyl which may have a substituent, (3) a C₃₋₆cycloalkyl which may have a substituent, (4) a C₆₋₁₄ aryl which may havea substituent, (5) a C₇₋₂₀ aralkyl which may have a substituent, (6) acarbamoyl which may have a substituent or (7) a heterocyclic group; andR^(f) is a hydrogen atom or a C₁₋₆ alkyl whish may have a substituent.

Examples of “C₁₋₆ alkyl” of “C₁₋₆ alkyl which may have a substituent”represented by R^(e) and R^(f) are methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like.

Examples of the substituent of “C₁₋₆ alkyl which may have a substituent”represented by R^(e) and R^(f) are (1) a C₁₋₆ alkyl (e.g., methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, hexyl, and the like), (2) a C₂₋₆ alkenyl (e.g., vinyl,1-methylvinyl, 1-propenyl, allyl, and the like), (3) a C₂₋₆ alkynyl(e.g., ethynyl, 1-propynyl, propargyl and the like), (4) a C₃₋₆cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andthe like), (5) a C₅₋₇ cycloalkenyl (e.g., cyclopentenyl, cyclohexenyl,and the like), (6) a C₇₋₁₁ aralkyl (e.g., benzyl, α-methylbenzyl,phenethyl, and the like), (7) a C₆₋₁₄ aryl (e.g., phenyl, naphthyl, andthe like), (8) a C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like),(9) a C₆₋₁₄ aryloxy (e.g., phenoxy, 1-naphthoxy, 2-naphthoxy, and thelike), (10) a C₁₋₆ alkanoyl (e.g., formyl, acetyl, propionyl, butyryl,isobutyryl, and the like), (11) a C₆₋₁₄ aryl-carbonyl (e.g., benzoyl,1-naphthylcarbonyl, 2-naphthylcarbonyl, and the like), (12) a C₁₋₆alkanoyloxy (e.g., formyloxy, acetoxy, propionyloxy, butyryloxy,isobutyryloxy, and the like), (13) a C₆₋₁₄ aryl-carbonyloxy (e.g.,benzoyloxy, 1-naphthylcarbonyloxy, 2-naphthylcarbonyloxy, and the like),(14) a carboxy, (16) a C₁₋₆ alkoxy-carbonyl (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl, tert-butoxycarbonyl, and the like), (16) a carbamoyl,(17) a N-mono-C₁₋₄ alkylcarbamoyl (e.g., N-methylcarbamoyl,N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl,N-butylcarbamoyl, and the like), (18) a N,N-di-C₁₋₄ alkylcarbamoyl(e.g., N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,N,N-dipropylcarbamoyl, N,N-dibutylcarbamoyl, and the like), (19) acyclic aminocarbonyl (e.g., 1-aziridinylcarbonyl, 1-azetidinylcarbonyl,1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl,N-methylpiperazinylcarbonyl, morpholinocarbonyl, and the like), (20) ahalogen (e.g., fluorine, chlorine, bromine, iodine), (21) a C₁₋₄ alkylsubstituted by 1 to 3 halogen(s) (e.g., chloromethyl, dichloromethyl,trifluoromethyl, trifluoroethyl, and the like), (22) an oxo, (23) anamidino, (24) an imino, (25) an amino, (26) a mono- or di-C₁₋₄alkylamino (e.g., methylamino, ethylamino, propylamino, isopropylamino,butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino,hexylamino, dimethylamino, diethylamino, dipropylamino, and the like),(27) a 3- to 6-membered cyclic amino which may contain 1 to 3heteroatom(s) selected from an oxygen atom, a sulfur atom, a nitrogenatom, and the like in addition to carbon atom (e.g., aziridinyl,azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl,imidazolidinyl, piperidino, morpholino, dihydropyridyl, pyridyl,N-methylpiperazinyl, N-ethylpiperazinyl, and the like), (28) a C₁₋₆alkanoylamino (e.g., formylamino, acetylamino, trifluoroacetylamino,propionylamino, butyrylamino, isobutyrylamino, and the like), (29) abenzamido, (30) carbamoylamino, (31) a (N—C₁₋₄ alkylcarbamoyl)amino(e.g., (N-methylcarbamoyl)amino, (N-ethylcarbamoyl)amino,(N-propylcarbamoyl)amino, (N-isopropylcarbamoyl)amino,(N-butylcarbamoyl)amino, and the like), (32) a (N,N-di-C₁₋₄alkylcarbamoyl)amino (e.g., (N,N-dimethylcarbamoyl)amino,(N,N-diethylcarbamoyl)amino, (N,N-dipropylcarbamoyl)amino,(N,N-dibutylcarbamoyl)amino, and the like), (33) a C₁₋₆ alkylenedioxy(e.g., —OCH₂O—, —O(CH₂)₂O—, —O(CH₂)₃O—, —O(CH₂)₄O—, —O(CH₂)₅O—,—O(CH₂)₆O—), (34) a dihydroboryl, (35) a hydroxy, (36) an epoxy, (37) anitro, (38) a cyano, (39) a mercapto, (40) a sulfo, (41) a sulfino, (42)a phosphono, (43) a sulfamoyl, (44) a N—C₁₋₆ alkylsulfamoyl (e.g.,N-methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl,N-isopropylsulfamoyl, N-butylsulfamoyl, and the like), (45) aN,N-di-C₁₋₆ alkylsulfamoyl (e.g., N,N-dimethylsulfamoyl,N,N-diethylsulfamoyl, N,N-dipropylsulfamoyl, N,N-dibutylsulfamoyl, andthe like), (46) a C₁₋₆ alkylthio (e.g., methylthio, ethylthio,propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, andthe like), (47) a phenylthio, (48) a C₁₋₆ alkylsulfinyl (e.g.,methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, and thelike), (49) a phenylsulfinyl, (50) a C₁₋₆ alkylsulfonyl (e.g.,methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, and thelike), (51) a phenylsulfonyl, and the like. The number of substituent is1 to 6, preferably 1 to 3, and the substitution position may be anyplace on which the substitution is possible.

Examples of “C₃₋₆ cycloalkyl” of “C₃₋₆ cycloalkyl which may have asubstituent” represented by R^(e) are cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and the like.

Examples of the substituent of “C₃₋₆ cycloalkyl which may have asubstituent” represented by R^(e) are the same as the substituent of“C₁₋₆ alkyl which may have a substituent” represented by R^(e) and R^(f)above. The number of substituents is 1 to 6, preferably 1 to 3, and thesubstitution position may be any place on which the substitution ispossible.

Examples of C₆₋₁₄ aryl of “C₆₋₁₄ aryl which may have a substituent”represented by R^(e) are phenyl, naphthyl, anthracenyl, and the like.

Examples of the substituent of “C₆₋₁₄ aryl which may have a substituent”are the same as the substituent of “C₁₋₆ alkyl which may have asubstituent” represented by R^(e) and R^(f) above except for oxo andepoxy. The number of substituents is 1 to 6, preferably 1 to 3, and thesubstitution position may be any place on which the substitution ispossible.

Examples of C₇₋₂₀ aralkyl of “C₇₋₂₀ aralkyl which may have asubstituent” represented by R^(e) are benzyl, phenethyl, phenylpropyl,benzhydroryl, trityl and the like.

Examples of the substituent of “C₇₋₂₀ aralkyl which may have asubstituent” are the same as the substituent of “C₁₋₆ alkyl which mayhave a substituent” represented by R^(e) and R^(f) above. The number ofsubstituent is 1 to 6, preferably 1 to 3, and the substitution positionmay be any place on which the substitution is possible.

Examples of the substituent of “carbamoyl which may have a substituent”represented by R^(e) are (1) a C₁₋₆ alkyl which may have a substituent,(2) a C₃₋₆ cycloalkyl which may have a substituent, (3) a C₆₋₁₄ arylwhich may have a substituent, (4) a C₇₋₂₀ aralkyl which may have asubstituent, (5) a hydroxy, (6) a C₁₋₆ alkoxy which may have asubstituent, (7) a C₁₋₆ alkoxy-carbonyl which may have a substituent,and the like. The number of the substituent may be 1 or 2.

Examples of “C₁₋₆ alkyl which may have a substituent” as a substituentof “carbamoyl which may have a substituent” represented by R^(e) are thesame as “C₁₋₆ alkyl which may have a substituent” represented by R^(e)and R^(f) above.

Examples of “C₃₋₆ cycloalkyl which may have a substituent”, “C₆₋₁₄ arylwhich may have a substituent” and “C₇₋₂₀ aralkyl which may have asubstituent” as a substituent of “carbamoyl which may have asubstituent” represented by R^(e) are the same as “C₃₋₆ cycloalkyl whichmay have a substituent”, “C₆₋₁₄ aryl which may have a substituent” and“C₇₋₂₀ aralkyl which may have a substituent” represented by R^(e) above.

Examples of the C₁₋₆ alkoxy of “C₁₋₆ alkoxy which may have asubstituent” as a substituent of “carbamoyl which may have asubstituent” represented by R^(e) are methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy,hexyloxy, and the like. Examples of the substituent of “C₁₋₆ alkoxywhich may have a substituent” are the same as the substituent of “C₁₋₆alkyl which may have a substituent” represented by R^(e) above. Thenumber of substituents is 1 to 6, preferably 1 to 3, and thesubstitution position may be any place on which the substitution ispossible.

Example of “C₁₋₆ alkoxy-carbonyl which may have a substituent” as asubstituent of “carbamoyl which may have a substituent” represented byR^(e) is a group comprising combining “C₁₋₆ alkoxy which may have asubstituent” as a substituent of “carbamoyl which may have asubstituent” represented by R^(e) above with carbonyl.

Examples of “heterocyclic group” represented by R^(e) are (1) a5-membered cyclic group containing 1 to 4 heteroatom(s) selected from anoxygen atom, a sulfur atom, a nitrogen atom, and the like in addition tocarbon atom (e.g., 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl,3-pyrrolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl,3-(1,2,4-oxadiazolyl), 5-(1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl,3-(1,2,4-thiadiazolyl), 5-(1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl,4-(1,2,3-thiadiazolyl), 5-(1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl,oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, and the like), (2) a6-membered cyclic group containing 1 to 4 heteroatom(s) selected from anoxygen atom, a sulfur atom, a nitrogen atom, and the like in addition tocarbon atom (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl, N-oxido-2-pyridyl,N-oxido-3-pyridyl, N-oxido-4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, N-oxido-2-pyrimidinyl, N-oxido-4-pyrimidinyl,N-oxido-5-pyrimidinyl, 2-thiomorpholinyl, 3-thiomorpholinyl,2-morpholinyl, 3-morpholinyl, piperidinyl, pyranyl, thiopyranyl,1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, 2-piperazinyl,3-piperazinyl, triazinyl, oxotriazinyl, 3-pyridazinyl, 4-pyridazinyl,pyrazinyl, N-oxido-3-pyridazinyl, N-oxido-4-pyridazinyl, and the like),and (3) a bicyclic or tricyclic condensed cyclic group which contains 1to 4 heteroatom(s) selected from an oxygen atom, a sulfur atom, anitrogen atom and the like in addition to a carbon atom (e.g.,benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo[1,5-b]pyridazinyl,triazolo[4,5-b]pyridazinyl, benzoimidazolyl, quinolyl, isoquinolyl,cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl,quinolizinyl, 1,8-naphthylidinyl, purinyl, pteridinyl, dibenzofuranyl,carbazolyl, acridinyl, phenanthrydinyl, chromanyl, benzoxazinyl,phenazinyl, phenothiazinyl, phenoxazinyl, and the like).

Examples of the aryl of “aryl which may have a substituent” representedby R^(d) are phenyl, naphthyl, anthracenyl, and the like.

Examples of the substituent of “aryl which may have a substituent”represented by R^(d) are (1) a C₆₋₁₄ aryl (e.g., phenyl, naphthyl, andthe like) which may have 1 to 4 substituent(s) selected from the groupconsisting of (i) a hydroxy, (ii) an amino, (iii) a mono- or di-C₁₋₆alkylamino (e.g., methylamino, ethylamino, propylamino, dimethylamino,diethylamino, and the like), (iv) a C₁₋₆ alkoxy (e.g., methoxy, ethoxy,propoxy, butoxy, pentyloxy, hexyloxy, and the like), and (v) a halogen(e.g., fluorine, chlorine, bromine and iodine), (2) a hydroxy, (3) acarboxy, (4) a nitro, (5) a C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy,isopropoxy, butoxy, pentyloxy, hexyloxy, and the like), (6) a C₁₋₆alkyl-carbonyloxy (e.g., acetoxy, propionyloxy, butyryloxy,isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy,pentylcarbonyloxy, hexylcarbonyloxy, and the like), (7) a C₁₋₆ alkylthio(e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio,isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio, andthe like), (8) a C₁₋₆ alkylsulfinyl (e.g., methylsulfinyl,ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl,isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, pentylsulfinyl,hexylsulfinyl, and the like), (9) a C₁₋₆ alkylsulfonyl (e.g.,methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl,butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl,pentylsulfonyl, hexylsulfonyl, and the like), (10) a halogen (e.g.,fluorine, chlorine, bromine and iodine), (11) a group of the formula:—NR^(g)R^(h) wherein R^(g) is (a) a hydrogen atom, (b) a C₁₋₆ alkylwhich may have a substituent, (c) a C₃₋₆ cycloalkyl which may have asubstituent, (d) a C₆₋₁₄ aryl which may have a substituent, (e) a C₇₋₂₀aralkyl which may have a substituent, (f) a carbamoyl which may have 1or 2 substituent(s) selected from the group consisting of (i) a C₃₋₆cycloalkyl which may have a substituent, (ii) a C₆₋₁₄ aryl which mayhave a substituent, (iii) a C₇₋₂₀ aralkyl which may have a substituent,(iv) hydroxy, (v) a C₁₋₆ alkoxy which may have a substituent and (vi) aC₁₋₆ alkoxy-carbonyl which may have a substituent, (g) a heterocyclicgroup; and R^(h) is a hydrogen atom or a C₁₋₆ alkyl which may have asubstituent, (12) a 5-membered cyclic group containing 1 to 4heteroatom(s) selected from an oxygen atom, a sulfur atom, a nitrogenatom, and the like in addition to carbon atom (e.g., 2-thienyl,3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-oxazolyl,4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl,4-isothiazolyl, 5-isothiazolyl, 3-(1,2,4-oxadiazolyl),5-(1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3-(1,2,4-thiadiazolyl),5-(1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4-(1,2,3-thiadiazolyl),5-(1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, oxoimidazinyl,dioxotriazinyl, pyrrolidinyl, and the like), (13) a 6-membered cyclicgroup containing 1 to 4 heteroatom(s) selected from an oxygen atom, asulfur atom, a nitrogen atom, and the like in addition to carbon atom(e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl, N-oxido-2-pyridyl,N-oxido-3-pyridyl, N-oxido-4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, N-oxido-2-pyrimidinyl, N-oxido-4-pyrimidinyl,N-oxido-5-pyrimidinyl, 2-thiomorpholinyl, 3-thiomorpholinyl,2-morpholinyl, 3-morpholinyl, piperidinyl, pyranyl, thiopyranyl,1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, 2-piperazinyl,3-piperazinyl, triazinyl, oxotriazinyl, 3-pyridazinyl, 4-pyridazinyl,pyrazinyl, N-oxido-3-pyridazinyl, N-oxido-4-pyridazinyl, and the like),(14) a bicyclic or tricyclic condensed cyclic group which contains 1 to4 heteroatom(s) selected from an oxygen atom, a sulfur atom, a nitrogenatom and the like in addition to a carbon atom (e.g., benzofuryl,benzothiazolyl, benzoxazolyl, tetrazolo[1,5-b]pyridazinyl,triazolo[4,5-b]pyridazinyl, benzoimidazolyl, quinolyl, isoquinolyl,cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl,quinolizinyl, 1,8-naphthylidinyl, purinyl, pteridinyl, dibenzofuranyl,carbazolyl, acridinyl, phenanthrydinyl, chromanyl, benzoxazinyl,phenazinyl, phenothiazinyl, phenoxazinyl, and the like), (15) a C₁₋₆alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl,hexyloxycarbonyl, and the like), (16) a carbamoyl, (17) a N-mono-C₁₋₆alkylcarbamoyl (e.g., N-methylcarbamoyl, N-ethylcarbamoyl,N-propylcarbamoyl, N-isopropylcarbamoyl, and the like), (18) aN,N-di-C₁₋₆ alkylcarbamoyl (e.g., N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl, and the like), and thelike. The number of substituent is 1 to 6, preferably 1 to 3, and thesubstitution position may be any place on which the substitution ispossible.

The definitions of R^(g) and R^(f) utilized in the group of the formula:—NR^(g)R^(h) wherein R^(g) and R^(h) have the same meanings definedabove as a substituent of “aryl which may have a substituent”represented by R^(d) are shown below.

Examples of “C₁₋₆ alkyl which may have a substituent” represented byR^(g) and R^(h) are the same as “C₁₋₆ alkyl which may have asubstituent” represented by R^(e) and R^(f) described above.

Examples of “C₃₋₆ cycloalkyl which may have a substituent”, “C₆₋₁₄ arylwhich may have a substituent”, “C₇₋₂₀ aralkyl which may have asubstituent” and “heterocyclic group” represented by R^(g) are the sameas “C₃₋₆ cycloalkyl which may have a substituent”, “C₆₋₁₄ aryl which mayhave a substituent”, “C₇₋₂₀ aralkyl which may have a substituent” and“heterocyclic group” represented by R^(e) described above.

Examples of “C₃₋₆ cycloalkyl which may have a substituent”, “C₆₋₁₄ arylwhich may have a substituent” and “C₇₋₂₀ aralkyl which may have asubstituent” of “carbamoyl which may have 1 or 2 substituent(s) selectedfrom the group consisting of (i) a C₃₋₆ cycloalkyl which may have asubstituent, (ii) a C₆₋₁₄ aryl which may have a substituent, (iii) aC₇₋₂₀ aralkyl which may have a substituent, (iv) a hydroxy, (v) a C₁₋₆alkoxy which may have a substituent and (vi) a C₁₋₆ alkoxy-carbonylwhich may have a substituent” represented by R^(g) are the same as “C₃₋₆cycloalkyl which may have a substituent”, “C₆₋₁₄ aryl which may have asubstituent” and “C₇₋₂₀ aralkyl which may have a substituent”represented by R^(e) described above.

Examples of “C₁₋₆ alkoxy which may have a substituent” of “carbamoylwhich may have 1 or 2 substituent(s) selected from the group consistingof (i) a C₃₋₆ cycloalkyl which may have a substituent, (ii) a C₆₋₁₄ arylwhich may have a substituent, (iii) a C₇₋₂₀ aralkyl which may have asubstituent, (iv) a hydroxy, (v) a C₁₋₆ alkoxy which may have asubstituent and (vi) a C₁₋₆ alkoxy-carbonyl which may have asubstituent” represented by R^(g) are methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy,hexyloxy, and the like.

Examples of the substituent of said “C₁₋₆ alkoxy which may have asubstituent” are the same as the substituent of “C₁₋₆ alkyl which mayhave a substituent” represented by R^(e) described above. The number ofsubstituents is 1 to 6, preferably 1 to 3, and the substitution positionmay be any place on which the substitution is possible.

Example of “C₁₋₆ alkoxy-carbonyl which may have a substituent” of“carbamoyl which may have 1 or 2 substituent(s) selected from the groupconsisting of (i) a C₃₋₆ cycloalkyl which may have a substituent, (ii) aC₆₋₁₄ aryl which may have a substituent, (iii) a C₇₋₂₀ aralkyl which mayhave a substituent, (iv) a hydroxy, (v) a C₁₋₆ alkoxy which may have asubstituent and (vi) a C₁₋₆ alkoxy-carbonyl which may have asubstituent” represented by R^(g) is a group comprising combining “C₁₋₆alkoxy which may have a substituent” as a substituent of “carbamoylwhich may have a substituent” represented by R⁹ above with carbonyl.

Preferable examples of R^(a) are an aryl group which may have 1 to 5substituent(s) selected from the group consisting of (i) a halogen, (ii)a nitro, (iii) a cyano, (iv) an amino, (v) a carboxyl group which may beesterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) analkoxy, (ix) an alkylthio, (x) an alkylsulfinyl and (xi) analkylsulfonyl. Among them, a phenyl which is mono- or di-substituted bya halogen, especially 2,6-difluorophenyl, are preferable.

Preferable examples of R^(b) are pyrrolidin-1-yl, pyrrolidin-2-yl,imidazol-1-yl, imidazol-2-yl, 1,2,3-triazol-1-yl, 1,2,5-triazol-1-yl,tetrazol-1-yl, tetrazol-2-yl, pyridin-2-yl, pyridin-4-yl. Among them,pyridin-2-yl is preferable.

Preferable example of R^(c) is a group represented by the formula:—NR^(e′)RF wherein R^(e′) is (1) a C₁₋₆ alkyl which may have asubstituent or (2) a C₇₋₂₀ aralkyl; RF is a C₁₋₆ alkyl. Among them, agroup of the formula: —N(Me)R^(e″) wherein R^(e″) is a C₁₋₆ alkyl whichis substituted by a C₁₋₆ alkoxy; or benzyl is preferable.

Preferable example of R^(d) is phenyl which may have a substituent.Among them, phenyl group which is substituted at its 4-position by agroup represented by the formula —NR^(g)R^(h): wherein each R^(g) andR^(h) has the meaning defined above, is preferable, and especially,phenyl group which is substituted at its 4-position by a grouprepresented by the formula —NHR^(g′) wherein R^(g′) is carbamoyl whichmay have 1 or 2 substituent(s) selected from the group consisting of (i)a C₃₋₆ cycloalkyl which may have a substituent, (ii) a C₆₋₁₄ aryl whichmay have a substituent, (iii) a C₇₋₂₀ aralkyl which may have asubstituent, (iv) hydroxy, (v) a C₁₋₆ alkoxy which may have asubstituent and (vi) a C₁₋₆ alkoxy-carbonylamino is preferable.Especially, a phenyl group substituted at its 4-position by a C₁₋₆alkoxyamino-carbonylamino (e.g. 4-methoxyaminocarbonylaminophenyl,4-ethoxyaminocarbonylaminophenyl, and the like) is more preferable.

p is preferably 1. And q is preferably 1.

Salts of Compound (A) are preferably physiologically acceptable acidaddition salts. Such salts include, for example, salts with inorganicacids (e.g., hydrochloric acid, hydrobromic acid, nitric acid, sulfuricacid, phosphoric acid), salts with organic acids (e.g., formic acid,acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaricacid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,etc.), and the like. When Compound (A) has an acidic group, it may forma physiologically acceptable salt with an inorganic base (e.g., alkalimetals and alkaline earth metals such as sodium, potassium, calcium andmagnesium, ammonia, and the like) or an organic base (e.g.,trimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,N,N′-dibenzylethylenediamine, and the like).

Compound (A) can be produced by the method described in JP-A-9-169768(WO 96/24597) and JP-A-2001-278884 (WO 00/56739) and its analogousmethod.

Compound (A) may be a hydrate or a non-hydrate. The hydrate isexemplified by monohydrate, sesquihydrate and dihydrate.

When Compound (A) is obtained as a mixture of optically activeconfigurations, it can be resolved into the (R)- and (S)-forms by theconventional optical resolution techniques.

Compound (A) can be used as a prodrug. The prodrug of Compound (A) or asalt thereof means a compound which is converted to Compound (A) of thepresent invention under physiological conditions or with a reaction dueto an enzyme, a gastric acid, and the like in the living body, that is,a compound which is converted to Compound (A) of the present inventionwith oxidation, reduction, hydrolysis, and the like with an enzyme; acompound which is converted to Compound (A) of the present inventionwith gastric acid, etc. The prodrug for Compound (A) may for example bea compound obtained by subjecting an amino group in Compound (A) to anacylation, alkylation or phosphorylation (e.g., a compound obtained bysubjecting an amino group in Compound (A) or to an eicosanoylation,alanylation, pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylationand tert-butylation, etc.); a compound obtained by subjecting a hydroxygroup in Compound (A) to an acylation, alkylation, phosphorylation orboration (e.g., a compound obtained by subjecting an hydroxy in Compound(A) to an acetylation, palmitoylation, propanoylation, pivaloylation,succinylation, fumarylation, alanylation,dimethylaminomethylcarbonylation, etc.); a compound obtained bysubjecting a carboxy group in Compound (A) to an esterification oramidation (e.g., a compound obtained by subjecting a carboxyl group incompound (A) to an ethylesterification, phenylesterification,carboxymethylesterification, dimethylaminomethylesterification,pivaloyloxymethylesterification, ethoxycarbonyloxyethylesterification,phthalidylesterification,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterification,cyclohexyloxycarbonylethylesterification and methylamidation, etc.) andthe like. Any of these compounds can be produced from the compound ofthe present invention by a method known per se.

A prodrug of Compound (A) may also be one which is converted intoCompound (A) under a physiological condition, such as those described in“IYAKUHIN no KAIHATSU (Development of Pharmaceuticals)”, Vol. 7, Designof Molecules, p. 163-198, Published by HIROKAWA SHOTEN (1990).

Compound (A) may be labeled with an isotope (e.g., ³H, ¹⁴C, ³⁵S) and thelike.

The present invention is hereinafter described in more detail by meansof, but is not limited to, the following Reference Examples, Examples,Preparation Examples and Experimental Examples.

¹H-NMR spectra are determined with tetramethylsilane as the internalstandard, using the Varian GEMINI 200 (200 MHz) spectrometer, the JEOLLAMBDA 300 (300 MHz) spectrometer or the Bruker AM500 (600 MHz)spectrometer; all 6 values are shown in ppm. Unless otherwisespecifically indicated, “%” is by weight. Yield indicates mol/mol %. Theother symbols used herein have the following definitions:

s: singlet

d: doublet

t: triplet

dt: double triplet

m: multiplet

br: broad

AIBN: 2,2-azobisisobutyronitrile

DMF: N,N-dimethylformamide

NBS: N-bromosuccinimide

TFA: trifluoroacetic acid

THF: tetrahydrofuran

Me: methyl

Et: ethyl

Ph: phenyl

TBS: tert-butyl dimethyl silyl

Ms: methanesulfonyl

The term “room temperature” indicates the range from about 15 to 25° C.,but is not to be construed as strictly limitative. Each of lactose, cornstarch, D-mannitol, low substituted hydroxypropylcellulose, talc,hydroxypropylcellulose, hydroxypropylmethylcellulose 2910, titaniumoxide and light silicic acid anhydride used in the following Preparationis suited for standard of Pharmacopoeia, Fourteenth Edition.

EXAMPLES Reference Example 1 Production of ethyl2-[(2,6-difluorobenzyl)(ethoxycarbonyl)amino]-5-(4-{[(methoxyamino)carbonyl]amino}phenyl)-4-[(methylamino)methyl]thiophene-3-carboxylate

To a solution of ethyl 4-(N-benzyl-N-methylaminomethyl)-2-[N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino]-5-[4-(3-methoxyureido)phenyl]thiophene-3-carboxylate(3.64 g, 5.47 mmol) in ethanol (100 ml) were added 1N hydrochloric acid(8 ml) and 10% palladium-carbon (50% wet, 1.82 g). The mixture wasstirred vigorously under hydrogen atmosphere for 6 hours. The catalystwas removed, and the filtrate was neutralized with 1N sodium hydroxidesolution. The solvent was distilled off, and the residue was distributedbetween ethyl acetate and water. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas distilled off under reduced pressure. The residue was subjected toan NH-silica gel (Fuji Silysia Chemical) chromatography to give thetitle compound (2.43 g, 77%) as yellow powders.

¹H-NMR (CDCl₃) δ: 1.18 (3H, t, J=7.0 Hz), 1.33 (3H, t, J=7.2 Hz), 2.33(3H, s), 3.65 (2H, s), 3.82 (5H, s), 4.16 (2H, q, J=7.0 Hz), 4.24 (2H,q, J=7.2 Hz), 4.96 (2H, s), 6.84 (2H, t, J=7.8 Hz), 7.1-7.35 (3H, m),7.44 (2H, d, J=8.6 Hz), 7.53 (2H, d, J=8.6 Hz), 7.63 (1H, s).

Reference Example 2 Production of ethyl2-[(2,6-difluorobenzyl)(ethoxycarbonyl)amino]-5-(4-{[(methoxyamino)carbonyl]amino}phenyl)-4-{[methyl(pyridin-2-ylmethyl)amino]methyl}thiophene-3-carboxylate

The compound obtained in Reference Example 1 (2.43 g, 4.21 mmol) wasdissolved in DMF (20 ml), and N,N-diisopropylethylamine (2.93 ml, 16.84mmol) and 2-chloromethylpyridine hydrochloride (1.04 g, 6.32 mmol) wereadded thereto. The mixture was stirred at room temperature for 24 hours,combined with saturated aqueous solution of sodium hydrogen carbonateand extracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: ethyl acetate) to give the title compound (2.34g, 83%) as yellow powders.

Reference Example 3 Production of2-[(2,6-difluorobenzyl)(ethoxycarbonyl)amino]-5-(4-{[(methoxyamino)carbonyl]amino}phenyl)-4-{[methyl(pyridin-2-ylmethyl)amino]methyl}thiophene-3-carboxylicacid

To a solution of the compound obtained in Reference Example 2 (2.34 g,3.5 mmol) in ethanol (40 ml) was added 2N sodium hydroxide solution(8.75 ml), and the mixture was stirred at 50-60° C. for 14 hours. Thereaction mixture was cooled to room temperature and neutralized with 1Nhydrochloric acid. The solvent was distilled off and the obtainedresidue was distributed between ethyl acetate and water. The organiclayer was washed with saturated brine and dried over magnesium sulfate.The solvent was distilled off under reduced pressure to give the titlecompound (2.06 g, 92%) as pale yellow powders.

¹H-NMR (CDCl₃) δ: 1.1-1.3 (3H, m), 2.28 (3H, s), 3.7-3.9 (2H, brm), 3.84(3H, s), 3.91 (3H, s), 4.1-4.3 (2H, m), 5.07 (2H, s), 6.7-6.85 (2H, m),7.15-7.8 (10H, m), 8.5-8.6 (1H, m).

Reference Example 4 Production of methyl 6-(bromomethyl)nicotinate

Methyl 6-methylnicotinate (1.05 g, 10 mmol) was dissolved in ethylacetate (50 ml), and NBS (3.56 g, 20 mmol) and AIBN (329 mg, 2 mmol)were added thereto. The reaction mixture was stirred at 80° C. for 3hours, combined with an aqueous solution of sodium hydrogen carbonateand extracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: ethyl acetate/hexane=1/4) to give the titlecompound (682 mg, 28%) as an orange amorphous compound.

¹H-NMR (CDCl₃) δ: 3.96 (3H, s), 4.58 (2H, s), 7.53 (1H, d, J=8.2 Hz),8.30 (2H, dd, J=1.8, 8.2 Hz), 9.17 (1H, d, J=1.8 Hz).

Reference Example 5 Production of ethyl2-[N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino]-4-[N-(2-methoxyethyl)-N-methylaminomethyl]-5-(4-aminophenyl)thiophene-3-carboxylate

A solution of 2N hydrochloride in diethyl ether (21 ml) and 10%palladium-carbon (50% wet, 3.73 g) were added to a solution of ethyl2-[N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino]-4-[N-(2-methoxyethyl)-N-methylaminomethyl]-5-(4-nitrophenyl)thiophene-3-carboxylate(12.43 g) (JP-A-2001-278884, WO 00/56739) in ethanol (315 ml). Themixture was stirred vigorously under hydrogen atmosphere for 1 hour. Thecatalyst was removed, and the filtrate was neutralized with sodiumhydrogen carbonate solution. The solvent was distilled off, and theresidue was distributed between ethyl acetate and water. The organiclayer was washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure. Theresidue was subjected to an NH-silica gel (Fuji Silysia Chemical)chromatography to give the title compound (11.44 g) as an oil.

¹H-NMR (CDCl₃) δ: 1.12-1.30 (3H, br), 2.05 (3H, s), 2.39 (2H, t, J=6.3Hz), 3.27 (3H, s), 3.32 (3H, t, J=6.3 Hz), 3.59 (2H, s), 3.78 (2H, s),4.20 (2H, q, J=7.1 Hz), 4.10-4.23 (2H, br), 5.00 (2H, s), 6.66 (2H, d,J=8.6 Hz), 6.84 (2H, t, J=8.2 Hz), 7.18 (2H, d, J=8.6 Hz), 7.15-7.30(1H, m).

IR (KBr): 1717, 1626, 1609, 1472, 1406, 1300, 1246 cm⁻¹.

Reference Example 6 Production of ethyl2-[(2,6-difluorobenzyl)(ethoxycarbonyl)amino]-5-(4-{[(methoxyamino)carbonyl]amino}phenyl)-4-{[(2-methoxyethyl)(methyl)amino]methyl}-3-thiophenecarboxylate

N-ethyldiisopropylamine (3.06 ml) was added to a solution of thecompound obtained in Reference Example 5 (4.89 g) in dichloromethane(113 ml) under ice cooling, and the mixture was stirred.N,N′-carbonyldiimidazole (2.82 g) was added to the mixture under icecooling. The reaction mixture was warmed to room temperature and stirredfor 67 hours. The reaction mixture was cooled under ice cooling, andO-methylhydroxyamine hydrochloride (7.26 g) and N-ethyldiisopropylamine(15.6 ml) were added thereto. The reaction mixture was warmed to roomtemperature and stirred at room temperature for 19 hours. The reactionmixture was distributed between chloroform and saturated aqueoussolution of sodium hydrogen carbonate, and extracted with chloroform.The combined extract was washed with brine and dried over magnesiumsulfate. The solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography to give thetitle compound (4.89 g) as a pale yellow caramelized product.

¹H-NMR (CDCl₃) δ: 1.19 (3H, brs), 1.30 (3H, t, J=6.9 Hz), 2.04 (3H, s),2.40 (2H, t, J=6.0 Hz), 3.27 (3H, s), 3.33 (2H, t, J=6.0 Hz), 3.60 (2H,s), 3.81 (3H, s), 4.13-4.24 (4H, m), 5.00 (2H, s), 6.84 (2H, t, J=7.8Hz), 7.19-7.29 (2H, m), 7.36 (2H, d, J=8.7 Hz), 7.50 (2H, d, J=8.7 Hz),7.60 (1H, s).

IR (KBr): 1717, 1590, 1528, 1472, 1408, 1304 cm⁻¹.

Reference Example 7 Production of2-[(2,6-difluorobenzyl)(ethoxycarbonyl)amino]-5-(4-{[(methoxyamino)carbonyl]amino}phenyl)-4-{[(2-methoxyethyl)(methyl)amino]methyl}-3-thiophenecarboxylicacid

An aqueous solution of 2N sodium hydroxide (18.9 ml) was added to asolution of the compound obtained in Reference Example 6 (4.81 g) inethanol (114 ml), and the mixture was stirred at 60° C. for 5 hours. Thereaction mixture was warmed to room temperature and combined with 1Nhydrochloric acid (37.8 ml). The solvent was distilled off. The residuewas dissolved in ethanol and toluene, and the solvent was distilled off.The residue was combined with anhydrous ethanol (30 ml), and theinorganic products were filtered off. The filtrate was concentrated todryness. The obtained residue was fined by anhydrous ether, collected byfiltration and dried to give the title compound (4.43 g).

¹H-NMR (CDCl₃) δ: 1.17 (3H, brs), 2.45 (3H, s), 2.81 (2H, brs), 3.28(3H, s), 3.55 (2H, t, J=4.8 Hz), 3.82 (3H, s), 3.92 (2H, s), 4.10-4.35(2H, m), 5.06 (2H, s), 6.82 (2H, t, J=7.8 Hz), 7.16 (2H, d, J=8.4 Hz),7.22-7.35 (1H, m), 7.60 (2H, d, J=8.4 Hz), 8.00-8.50 (2H, br).

IR (KBr): 1713, 1605, 1528, 1472, 1408 cm⁻¹.

Reference Example 8 Production of 4-(1-hydroxy-1-methylethyl)aniline (1)and 4-(1-methoxy-1-methylethyl)aniline (2)

To a solution of 2-methyl-2-(4-nitrophenyl)-2-propanol (2.0 g) inmethanol (55 ml) was added 5% platinum-carbon (0.3 g), and the mixturewas stirred under hydrogen atmosphere for 4 hours. The catalyst wasfiltered off, and the filtrate was concentrated to dryness. The obtainedresidue was purified by aminopropylsilica gel column chromatography(Fuji Silysia Chemical) (120 g; eluent hexane/ethyl acetate 9/1 to 1/4)to give 4-(1-hydroxy-1-methylethyl)aniline (1) (1.0 g) and4-(1-methoxy-1-methylethyl)aniline (2) (0.35 g).

4-(1-hydroxy-1-methylethyl)aniline (1)

¹H-NMR (CDCl₃) δ: 1.45 (1H, s), 1.55 (6H, s), 3.64 (2H, brs), 6.66 (2H,d, J=8.8 Hz), 7.28 (2H, d, J=8.8 Hz).

IR (KBr): 3335, 2975, 1613, 1516, 1256 cm⁻¹.

4-(1-methoxy-1-methylethyl)aniline (2)

¹H-NMR (CDCl₃) δ: 1.49 (6H, s), 3.03 (3H, s), 3.64 (2H, brs), 6.67 (2H,d, J=8.7 Hz), 7.20 (2H, d, J=8.7 Hz).

IR (KBr): 2978, 1630, 1613, 1518, 1358, 1264 cm⁻¹.

Reference Example 9 Production of 3-methoxy-6-methyl-2-nitropyridine

Potassium carbonate (4.15 g) and methyl iodide (2.80 ml) were added to asolution of 6-methyl-2-nitro-3-hydroxypyridine (4.63 g) in DMF (120 ml),and the mixture was stirred at room temperature for 14 hours. Thereaction mixture was distributed between ethylacetate and water. Theorganic layer was washed with saturated brine and dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure,and the residue was recrystallized from ethyl acetate/hexane to give thetitle compound (3.94 g) as needle crystals.

¹H-NMR (CDCl₃) δ: 2.54 (3H, s), 3.95 (3H, s), 7.37 (1H, d, J=8.8 Hz),7.44 (1H, d, J=8.8 Hz).

IR (KBr): 1541, 1489, 1381, 1308, 1289 cm⁻¹.

Reference Example 10 Production of 2-amino-3-methoxy-6-methylpyridine

To a solution of 3-methoxy-6-methyl-2-nitropyridine (3.85 g) in ethanol(91.6 ml) was added 10% palladium-carbon (50% wet, 0.96 g), and themixture was stirred under hydrogen atmosphere for 2 hours. The catalystwas filtered off, and the filtrate was concentrated to dryness. Theresidue was recrystallized from ethyl acetate/hexane to give the titlecompound (2.89 g).

¹H-NMR (CDCl₃) δ: 2.32 (3H, s), 3.81 (3H, s), 4.61 (2H, s), 6.44 (1H, d,J=8.4 Hz), 6.81 (1H, d, J=8.4 Hz).

IR (KBr): 1624, 1576, 1480, 1439, 1258 cm⁻¹.

Reference Example 11 Production of 2-amino-3-hydroxy-6-methylpyridine

The similar reaction as described in Reference Example 10 by using6-methyl-2-nitro-3-hydroxypyridine (4.63 g) gave the title compound(2.81 g) as crystalline powders.

¹H-NMR (DMSO-d₆) δ: 2.14 (3H, s), 5.29 (2H, s), 6.20 (1H, d, J=7.5 Hz),6.70 (1H, d, J=7.5 Hz), 9.09 (1H, s).

Reference Example 12 Production of 3-methoxy-2-nitropyridine

The similar reaction as described in Reference Example 9 by using2-nitro-3-hydroxypyridine (7.0 g), potassium carbonate (6.91 g) andmethyl iodide (4.67 ml) gave the title compound (7.5 g) as crystallinepowders.

¹H-NMR (CDCl₃) δ: 3.99 (3H, s), 7.54-7.56 (2H, m), 8.09-8.12 (1H, m).

IR (KBr): 1601, 1537, 1530, 1422, 1364, 1275 cm⁻¹.

Reference Example 13 Production of 2-amino-3-methoxypyridine

The similar reaction as described in Reference Example 10 by using3-methoxy-2-nitropyridine (7.5 g) gave the title compound (5.42 g) ascrystalline powders.

¹H-NMR (CDCl₃) δ: 3.84 (3H, s), 4.65 (2H, brs), 6.62 (1H, d, J=5.0 Hz,7.6 Hz), 6.90 (1H, dd, J=1.4 Hz, 7.6 Hz), 7.66 (1H, dd, J=1.4 Hz, 5.0Hz).

IR (KBr): 3443, 3142, 1634, 1601, 1570, 1483, 1460, 1441 cm⁻¹.

Example 1 Production ofN-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-2,4-dioxo-3-(2-pyridinyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

Ethyldiisopropylamine (1.05 ml, 6.02 mmol) and diethyl cyanophosphate(0.86 ml, 5.64 mmol) were added to a solution of4-(N-benzyl-N-methylaminomethyl)-2-[N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino]-5-[4-(3-methoxyureido)phenyl]thiophene-3-carboxylicacid (2.40 g, 3.76 mmol) and 2-aminopyridine (1.06 g, 11.28 mmol) in DMF(20 ml), and the mixture was stirred at room temperature for 3 days. Thereaction mixture was combined with sodium hydrogen carbonate solutionand extracted with ethyl acetate. The organic layer was washed withbrine, dried over magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: ethyl acetate) to give an amide compound. The obtained amidecompound was dissolved in methanol (40 ml), and sodium methoxide (2.03mg, 37.6 mmol) was added thereto. The reaction mixture was stirred atroom temperature for 5 hours, concentrated, neutralized with 1Nhydrochloric acid and extracted with ethyl acetate. The organic layerwas washed with brine, dried over magnesium sulfate and concentratedunder reduced pressure. The residue was purified by NH-silica gel columnchromatography (Fuji Silysia Chemical) (eluent: ethyl acetate) to givethe title compound (1.59 g, 63%) as a pale yellow amorphous compound.

¹H-NMR (CDCl₃) δ: 2.05 (3H, s), 3.56 (2H, s), 3.82 (3H, s), 3.89 (2H,s), 5.34 (2H, brs), 6.91 (2H, t, J=8.0 Hz), 7.1-7.45 (9H, m), 7.56 (2H,d, J=8.8 Hz), 7.65 (1H, s), 7.75 (2H, d, J=8.8 Hz), 7.91 (1H, dt, J=2.0,7.7 Hz), 8.7-8.75 (1H, m).

Elemental analysis for C₃₅H₃₀F₂N₆O₄S₂

Calcd.: C, 62.86; H, 4.52; N, 12.57.

Found: C, 62.72; H, 4.31; N, 12.40.

mp 179-182° C.

Reference Example 14 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-((methylamino)methyl)-2,4-dioxo-3-(2-pyridinyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

To a solution of the compound obtained in Example 1 (1.59 g, 2.38 mmol)in ethanol (40 ml) were added 1N hydrochloric acid (7 ml) and 10%palladium-carbon (60% wet, 0.63 g), and the mixture was stirredvigorously under hydrogen atmosphere for 20 hours. The catalyst wasremoved, and the filtrate was neutralized with 1N sodium hydroxidesolution. The solvent was distilled off. The residue was distributedbetween ethyl acetate and water, and the organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas distilled off, and the obtained powders were washed with diethylether to give the title compound (980 mg, 71%) as pale yellow powders.

¹H-NMR (CDCl₃) δ: 2.34 (3H, s), 3.78 (2H, s), 3.82 (2H, s), 5.38 (2H,brs), 6.92 (2H, t, J=8.2 Hz), 7.2-7.8 (9H, m), 7.92 (1H, dt, J=1.8 Hz,7.6 Hz), 8.72 (1H, d, J=4.8 Hz).

Example 2 Production ofN-{2-[{[1-(2,6-difluorobenzyl)-6-(4-{[(methoxyamino)carbonyl]amino}phenyl)-2,4-dioxo-3-(2-pyridinyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl]methyl}(methyl)amino]ethyl}-N-methylsulfonamide

2-(Methylamino)ethanol (0.14 g, 1.903 mmol) was dissolved in THF (10ml), and triethylamine (0.58 ml, 4.15 mmol) and methanesulfonyl chloride(0.27 ml, 3.46 mmol) were added thereto. The reaction mixture wasstirred at room temperature for 1 hour. The reaction mixture wascombined with an aqueous solution of sodium hydrogen carbonate andextracted with ethyl acetate. The water layer was salted out andextracted with ethyl acetate. The combined organic layer was dried overmagnesium sulfate and concentrated under reduced pressure to give amesylate. A solution of the obtained mesylate, the compound obtained inReference Example 14 (200 mg, 0.346 mmol), N,N-diisopropylethylamine(0.12 ml, 0.692 mmol) and potassium iodide (230 mg, 1.38 mmol) in DMF (8ml) was stirred at 50-60° C. for 16 hours. The reaction mixture wascombined with an aqueous solution of sodium hydrogen carbonate andextracted with ethyl acetate. The organic layer was washed with brine,dried over magnesium sulfate and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:ethyl acetate/methanol=80/1) and recrystallized fromdichloromethane/methanol/diethyl ether to give the title compound (115mg, 47%) as pale yellow crystals.

¹H-NMR (CDCl₃) δ: 2.11 (3H, s), 2.45-2.6 (2H, m), 2.70 (3H, s), 2.75(3H, s), 3.1-3.25 (2H, m), 3.80 (2H, s), 3.83 (3H, s), 5.36 (2H, brs),6.93 (2H, t, J=8.2 Hz), 7.14 (1H, s), 7.2-7.6 (7H, m), 7.65 (1H, s),7.85-7.95 (1H, m), 8.65-8.75 (1H, m).

IR (KBr): 1715, 1669, 1530, 1462, 1333, 1146, 1032, 781 cm⁻¹.

Elemental analysis for C₃₂H₃₃F₂N₇O₆S₂.0.3H₂O

Calcd.: C, 53.44; H, 4.71; N, 13.63.

Found: C, 53.76; H, 4.75; N, 13.21.

mp 185-187° C.

Example 3 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-((methyl(2-(2-oxo-1-pyrrolidinyl)ethyl)amino)methyl)-2,4-dioxo-3-(2-pyridinyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 2 by using the compoundobtained in Reference Example 14 (200 mg, 0.346 mmol) and1-(2-hydroxyethyl)-2-pyrrolidone (0.25 g, 1.903 mmol) gave the titlecompound (97 mg, 41%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.7-1.85 (2H, m), 2.17 (3H, s), 2.15-2.3 (2H, m),2.5-2.6 (2H, m), 3.15 (2H, t, J=7.0 Hz), 3.2-3.4 (2H, m), 3.76 (2H, s),3.83 (3H, s), 5.36 (2H, brs), 6.93 (2H, t, J=8.4 Hz), 7.16 (1H, s),7.2-7.7 (8H, m), 7.85-7.95 (1H, m), 8.65-8.75 (1H, m).

IR (KBr): 1715, 1672, 1526, 1464, 1329, 1032, 783 cm⁻¹.

Elemental analysis for C₃₄H₃₃F₂N₇O₅S.0.5H₂O

Calcd.: C, 58.44; H, 4.90; N, 14.03.

Found: C, 58.75; H, 4.98; N, 13.71.

mp 199-201° C.

Example 4 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-((methyl(2-pyridinylmethyl)amino)methyl)-2,4-dioxo-3-(2-pyridinyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The compound obtained in Reference Example 14 (150 mg, 0.259 mmol) wasdissolved in DMF (4 ml), and N,N-diisopropylethylamine (0.20 ml, 1.14mmol) and 2-chloromethylpyridine hydrochloride (85 mg, 0.518 mmol) wereadded thereto. The reaction mixture was stirred at room temperature for1 hour, combined with an aqueous solution of sodium hydrogen carbonateand extracted with ethyl acetate. The organic layer was washed withbrine, dried over magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: ethyl acetate/methanol=40/1), and recrystallized fromdichloromethane/methanol/diethyl ether to give the title compound (70mg, 40%) as pale yellow crystals.

¹H-NMR (CDCl₃) δ: 2.10 (3H, s), 3.70 (2H, s), 3.82 (3H, s), 3.96 (3H,s), 5.34 (2H, brs), 6.85-7.7 (14H, m), 7.85-7.95 (1H, m), 8.4-8.5 (1H,m), 8.65-8.75 (1H, m).

IR (KBr): 1717, 1672, 1526, 1464, 1331, 1236, 1036, 772 cm⁻¹.

Elemental analysis for C₃₄H₂₉F₂N₇O₄S.0.3H₂O

Calcd.: C, 62.36; H, 4.58; N, 12.47.

Found: C, 62.22; H, 4.32; N, 12.57.

mp 165-167° C.

Example 5 Production ofN-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-3-(2-hydroxyethyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

Ethyldiisopropylamine (0.56 ml, 3.2 mmol) and diethylcyanophosphate(0.46 ml, 3 mmol) were added to a solution of4-(N-benzyl-N-methylaminomethyl)-2-[N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino]-5-[4-(3-methoxyureido)phenyl]thiophene-3-carboxylicacid (1.28 g, 2 mmol) and 2-aminoethanol (183 mg, 3 mmol) in DMF (12ml), and the mixture was stirred at room temperature for 3 days. Thereaction mixture was combined with an aqueous solution of sodiumhydrogen carbonate, extracted with ethyl acetate, dried over magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by NH-silica gel column chromatography (Fuji Silysia Chemical)(eluent: ethyl acetate/methanol=80/1) to give an amide. The obtainedamide was dissolved in methanol (20 ml), and sodium methoxide (589 mg,10.9 mmol) was added thereto. The reaction mixture was stirred at 50-60°C. for 3 hours, concentrated under reduced pressure, neutralized with 1Nhydrochloric acid and extracted with ethyl acetate. The extract waswashed with brine, dried over magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: ethyl acetate) and recrystallized fromdichloromethane/methanol/diethyl ether to give the title compound (511mg, 74%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 2.04 (3H, s), 2.5-2.65 (1H, m), 3.58 (2H, s), 3.83(3H, s), 3.91 (2H, s), 3.9-4.0 (2H, m), 4.37 (2H, t, J=5.0 Hz), 5.34(2H, s), 6.92 (2H, t, J=8.2 Hz), 7.1-7.4 (7H, m), 7.54 (2H, d, J=8.6Hz), 7.66 (2H, d, J=8.6 Hz), 7.6-7.7 (1H, m).

IR (KBr): 1711, 1649, 1535, 1470, 1323, 1236, 1028, 785 cm⁻¹.

Elemental analysis for C₃₂H₃₁F₂N₅O₅S.0.5H₂O

Calcd.: C, 59.62; H, 5.00; N, 10.86.

Found: C, 59.75; H, 4.81; N, 10.93.

Example 6 Production ofN-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-2,4-dioxo-3-(2-(2H-1,2,3-triazol-2-yl)ethyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea(1)

Production ofN-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-2,4-dioxo-3-(2-(1H-1,2,3-triazol-1-yl)ethyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea(2)

The similar reaction as described in Example 2 by using the compoundobtained in Example 5 (450 mg, 0.708 mmol) gave a mesylate. A solutionof the obtained mesylate, 1,2,3-triazole (148 mg, 2.12 mmol andpotassium carbonate (294 mg, 2.12 mmol) in DMF (8 ml) was stirred atroom temperature for 18 hours, and at 50-60° C. for 3 hours. Thereaction mixture was combined with an aqueous solution of sodiumhydrogen carbonate and extracted with ethyl acetate. The organic layerwas washed with brine, dried over magnesium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent: ethyl acetate) to give the title compound 2-ylform (243 mg, 50%) as a white amorphous compound. On the other hand, theresidue was recrystallized from dichloromethane/methanol/diethyl etherto give the title compound 1-yl form (177 mg, 36%) as colorlesscrystals.

2-yl form (1)

¹H-NMR (CDCl₃) δ: 2.04 (3H, s), 3.51 (2H, s), 3.82 (3H, s), 3.86 (2H,s), 4.57 (2H, t, J=6.2 Hz), 4.81 (2H, t, J=6.2 Hz), 5.28 (2H, s), 6.91(2H, t, J=8.4 Hz), 7.15-7.35 (6H, m), 7.46 (2H, s), 7.53 (2H, d, J=8.6Hz), 7.62 (1H, s), 7.70 (2H, t, J=8.6 Hz), 7.75 (1H, s).

IR (KBr): 1705, 1663, 1530, 1472, 1323, 1034, 786 cm⁻¹.

1-yl form (2)

¹H-NMR (CDCl₃) δ: 2.02 (3H, s), 3.52 (2H, s), 3.82 (3H, s), 3.85 (2H,s), 4.58 (2H, t, J=6.4 Hz), 4.78 (2H, t, J=6.4 Hz), 5.30 (2H, s), 6.92(2H, t, J=8.2 Hz), 7.12 (1H, s), 7.15-7.4 (7H, m), 7.54 (2H, d, J=8.8Hz), 7.55-7.65 (2H, m), 7.67 (2H, d, J=8.8 Hz).

IR (KBr): 1709, 1659, 1526, 1472, 1319, 1028, 799 cm⁻¹.

Elemental analysis for C₃₄H₃₂F₂N₈O₄S.0.8H₂O

Calcd.: C, 58.24; H, 4.83; N, 15.98.

Found: C, 58.48; H, 4.89; N, 15.65.

Example 7 Production ofN-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-2,4-dioxo-3-(2-(2H-tetrazol-2-yl)ethyl)-1,2,3,4-tetrazolothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea(1)

Production ofN-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-2,4-dioxo-3-(2-(1H-tetrazol-1-yl)ethyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea(2)

The similar reaction as described in Example 6 by using the compoundobtained in Reference Example 5 (636 mg, 1 mmol) and tetrazole (210 mg,3 mmol) gave the title compound 2-yl form (234 mg, 34%) as a whiteamorphous compound. On the other hand, the residue was powdered bydiethylether to give the title compound, 1-yl form, (34 mg, 5%) as paleyellow crystals.

2-yl form (1)

¹H-NMR (CDCl₃) δ: 2.02 (3H, s), 3.51 (2H, s), 3.83 (5H, s), 4.6-4.7 (2H,m), 5.0-5.1 (2H, m), 5.28 (2H, s), 6.92 (2H, t, J=8.2 Hz), 7.12 (1H, s),7.2-7.75 (11H, m), 8.38 (1H, s).

IR (KBr): 1705, 1663, 1530, 1472, 1323, 1236, 1032, 777 cm⁻¹.

1-yl form (2)

¹H-NMR (CDCl₃) δ: 2.01 (3H, s), 3.51 (2H, s), 3.83 (3H, s), 3.8-4.0 (2H,m), 4.6-4.7 (2H, m), 4.8-4.9 (2H, m), 5.30 (2H, s), 6.65-6.75 (1H, m),6.85-7.0 (2H, m), 7.1-7.7 (11H, m), 8.68 (1H, s).

Example 8 Production ofN-(4-(1-(2,6-difluorobenzyl)-3-(2-hydroxyethyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 6 by using4-(N-benzyl-N-methylaminomethyl)-2-[N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino]-5-[4-(3-methoxyureido)phenyl]thiophen-3-carboxylicacid (1.21 g, 2 mmol) and 2-aminoethanol (0.18 ml, 3 mmol) to give thetitle compound (302 mg, 25%) as a pale yellow amorphous compound.

¹H-NMR (CDCl₃) δ: 2.11 (3H, s), 2.65 (2H, t, J=5.8 Hz), 3.30 (3H, s),3.46 (2H, t, J=5.8 Hz), 3.82 (5H, s), 3.9-4.0 (2H, m), 4.35 (2H, t,J=5.2 Hz), 5.34 (2H, s), 6.92 (2H, t, J=8.0 Hz), 7.14 (1H, s), 7.2-7.35(1H, m), 7.5-7.65 (5H, m).

Example 9 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-3-(2-(2H-tetrazol-2-yl)ethyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea(1)

Production ofN-(4-(1-(2,6-difluorobenzyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-3-(2-(H-tetrazol-1′-yl)ethyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea(2)

The similar reaction as described in Example 6 by using the compoundobtained in Example 8 (250 mg, 0.414 mmol) and tetrazole (145 mg, 2.07mmol) gave the title compound 2-yl form (66 mg, 24%) and 1-yl form (27mg, 10%) as white amorphous compounds.

2-yl form (1)

¹H-NMR (CDCl₃) δ: 2.10 (3H, brs), 2.55-2.65 (2H, m), 3.31 (3H, s),3.4-3.5 (2H, m), 3.76 (2H, s), 3.82 (3H, s), 4.62 (2H, t, J=5.8 Hz),5.02 (2H, t, J=5.8 Hz), 5.27 (2H, s), 6.92 (2H, t, J=8.2 Hz), 7.13 (1H,s), 7.25-7.4 (1H, m), 7.5-7.65 (5H, m), 8.43 (1H, s).

1-yl form (2)

¹H-NMR (CDCl₃) δ: 2.07 (3H, s), 2.55-2.65 (2H, m), 3.30 (3H, s), 3.4-3.5(2H, m), 3.74 (2H, s), 3.82 (3H, s), 4.55-4.65 (2H, m), 4.8-4.9 (2H, m),5.30 (2H, s), 6.93 (2H, t, J=7.8 Hz), 7.10 (1H, s), 7.2-7.4 (1H, m),7.5-7.65 (5H, m), 8.69 (1H, s).

Example 10 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-3-(2-(2H-1,2,3-triazol-2-yl)ethyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Reference Example 14 by using thecompound obtained in Example 6 (1-yl form) (200 mg, 0.291 mmol) gavede-benzyl-form (0.11 g, 63%) as colorless powders. The similar reactionas described in Example 4 by using the de-benzyl-form (0.11 g, 0.184mmol) and 2-(chloromethyl)methylether (0.10 ml, 1.104 mmol) gave thetitle compound (35 mg, 29%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 2.11 (3H, s), 2.62 (2H, t, J=5.8 Hz), 3.31 (3H, s),3.44 (2H, t, J=5.8 Hz), 3.78 (2H, s), 3.82 (3H, s), 4.55 (2H, t, J=5.6Hz), 4.79 (2H, t, J=5.6 Hz), 5.27 (2H, s), 6.91 (2H, t, J=8.2 Hz), 7.10(1H, s), 7.2-7.4 (2H, m), 7.51 (2H, s), 7.45-7.65 (4H, m).

Elemental analysis for C₃₀H₃₂F₂N₈O₅S

Calcd.: C, 55.04; H, 4.93; N, 17.12.

Found: C, 55.02; H, 4.85; N, 16.83.

Reference Example 15 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-((methylamino)methyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Reference Example 14 by using5-(N-benzyl-N-methylaminomethyl)-1-(2,6-difluorobenzyl)-6-[4-(3-methoxyureido)phenyl]-3-phenylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione (6.68 g, 10 mmol) gave the title compound (5.52 g, 96%) aswhite powders.

¹H-NMR (CDCl₃) δ: 2.35 (3H, s), 3.76 (2H, s), 3.82 (3H, s), 5.37 (2H,s), 6.92 (2H, t, J=8.2 Hz), 7.25-7.7 (12H, m).

Example 11 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-((methyl(2-(2H-1,2,3-triazol-2-yl)ethyl)amino)methyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea(1)

Production ofN-(4-(1-(2,6-difluorobenzyl)-5-((methyl(2-(1H-1,2,3-triazol-1-yl)ethyl)amino)methyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea(2)

Potassium carbonate (1.33 g, 10 mmol) was added to a solution of1,2,3-triazole (0.46 g, 6.67 mmol) and 1-bromo-2-chloroethane (0.83 ml,10 mmol) in DMF (5 ml), and the mixture was stirred at room temperaturefor 1 hour, and 50-60° C. for 3 hours. The reaction mixture was combinedwith saturated brine and extracted twice with ethyl acetate. Thecombined organic layer was dried over magnesium sulfate and concentratedto give a halide.

The compound obtained in Reference Example 15 (700 mg, 1.21 mmol) wasdissolved in DMF (12 ml), and N,N-diisopropylethylamine (1.16 ml, 6.67mmol) and the halide obtained above were added thereto. The mixture wasstirred at 50-60° C. for 16 hours, combined with an aqueous solution ofsodium hydrogen carbonate and extracted with ethyl acetate. The organiclayer was washed with brine, dried over magnesium sulfate andconcentrated under reduced pressure. The residue was purified byNH-silica gel column chromatography (eluent: ethyl acetate) andrecrystallized from dichloromethane/methanol/diethyl ether to give thetitle compound 2-yl form (140 mg, 17%) and 1-yl form (332 mg, 41%) ascolorless crystals.

2-yl form (1)

¹H-NMR (CDCl₃) δ: 2.23 (3H, s), 3.00 (2H, t, J=6.3 Hz), 3.78 (2H, s),3.82 (3H, s), 4.45 (2H, t, J=6.3 Hz), 5.37 (2H, s), 6.92 (2H, t, J=8.2Hz), 6.85-6.95 (1H, m), 7.11 (1H, s), 7.2-7.6 (12H, m).

IR (KBr): 1715, 1671, 1530, 1470, 1331, 1236, 1032, 822, 735 cm⁻¹.

Elemental analysis for C₃₃H₃₀F₂N₈O₄S.0.3H₂O

Calcd.: C, 58.45; H, 4.55; N, 16.52.

Found: C, 58.75; H, 4.27; N, 16.20.

mp 166-168° C.

1-yl form (2)

¹H-NMR (CDCl₃) δ: 2.14 (3H, s), 2.82 (2H, t, J=6.0 Hz), 3.80 (2H, s),3.82 (3H, s), 4.39 (2H, t, J=6.0 Hz), 5.37 (2H, s), 6.92 (2H, t, J=8.2Hz), 6.85-6.95 (1H, m), 7.14 (1H, s), 7.2-7.55 (11H, m), 7.63 (1H, s).

IR (KBr): 1719, 1672, 1526, 1470, 1236, 1231, 1028, 824, 733 cm⁻¹.

Elemental analysis for C₃₃H₃₀F₂N₈O₄S.0.4H₂O

Calcd.: C, 58.30; H, 4.57; N, 16.48.

Found: C, 58.53; H, 4.50; N, 16.29.

mp 194-196° C.

Example 12 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-((methyl(2-(2-pyridinyl)ethyl)amino)methyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 2 by using the compoundobtained in Reference Example 15 (350 mg, 0.606 mmol) and2-(2-hydroxyethyl)pyridine (0.45 g, 3.64 mmol) gave the title compound(233 mg, 56%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 2.20 (3H, s), 2.85 (4H, s), 3.82 (5H, s), 5.37 (2H,s), 6.93 (2H, t, J=8.2 Hz), 6.95-7.1 (2H, m), 7.14 (1H, s), 7.2-7.55(11H, m), 7.60 (1H, s), 8.43 (1H, d, J=4.0 Hz).

IR (KBr): 1717, 1667, 1530, 1470, 1331, 1236, 1030, 735 cm⁻¹.

Elemental analysis for C₃₆H₃₂F₂N₆O₄S

Calcd.: C, 63.33; H, 4.72; N, 12.31.

Found: C, 63.17; H, 4.56; N, 12.31.

mp 159-160° C.

Example 13 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-((methyl(2-(4-pyridinyl)ethyl)amino)methyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 2 by using the compoundobtained in Reference Example 15 (350 mg, 0.606 mmol) and4-(2-hydroxyethyl)pyridine hydrochloride (0.58 g, 3.64 mmol) gave thetitle compound (166 mg, 40%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 2.18 (3H, s), 2.68 (4H, s), 3.83 (5H, s), 5.37 (2H,s), 6.85-7.0 (5H, m), 7.16 (1H, s), 7.2-7.65 (10H, m), 8.35-8.4 (2H, m).

IR (KBr): 1715, 1667, 1532, 1470, 735 cm⁻¹.

Elemental analysis for C₃₆H₃₂F₂N₆O₄S.0.1H₂O

Calcd.: C, 63.16; H, 4.74; N, 12.28.

Found: C, 62.91; H, 4.68; N, 12.26.

mp 194-196° C.

Example 14 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-((methyl(2-pyridinylmethyl)amino)methyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 4 by using the compoundobtained in Reference Example 15 (350 mg, 0.606 mmol) and2-chloromethylpyridine hydrochloride (149 mg, 0.908 mmol) gave the titlecompound (297 mg, 73%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 2.10 (3H, s), 3.71 (2H, s), 3.83 (3H, s), 3.99 (2H,s), 5.36 (2H, s), 6.92 (2H, t, J=8.2 Hz), 7.0-7.1 (1H, m), 7.15 (1H, s),7.2-7.35 (4H, m), 7.4-7.65 (9H, m), 8.4-8.5 (1H, m).

IR (KBr): 1715, 1667, 1532, 1472, 735 cm⁻¹.

Elemental analysis for C₃₅H₃₀F₂N₆O₄S.0.5H₂O

Calcd.: C, 62.03; H, 4.61; N, 12.40.

Found: C, 62.13; H, 4.59; N, 12.47.

mp 181-182° C.

Reference Example 16 Production ofN-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-2,4-dioxo-3-(4-fluorophenyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 5 by using4-(N-benzyl-N-methylaminomethyl)-2-[N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino]-5-[4-(3-methoxyureido)phenyl]thiophene-3-carboxylicacid (2.87 g, 4.49 mmol) and 4-fluoroaniline (0.64 ml, 6.735 mmol) gavethe title compound (2.71 g, 88%) as pale yellow powders.

¹H-NMR (CDCl₃) δ: 2.05 (3H, s), 3.56 (2H, s), 3.83 (3H, s), 3.89 (2H,s), 5.36 (2H, s), 6.93 (2H, t, J=8.0 Hz), 7.1-7.35 (11H, m), 7.56 (2H,d, J=8.4 Hz), 7.63 (1H, s), 7.72 (2H, d, J=8.4 Hz).

Elemental analysis for C₃₆H₃₀F₃N₅O₄S.0.5H₂O

Calcd.: C, 62.24; H, 4.50; N, 10.08.

Found: C, 62.43; H, 4.21; N, 9.84.

Reference Example 17 Production ofN-(4-(1-(2,6-difluorobenzyl)-3-(4-fluorophenyl)-5-((methylamino)methyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Reference Example 14 by using thecompound obtained in Reference Example 16 (2.50 g, 3.65 mmol) gave thetitle compound (1.85 g, 85%) as white powder.

¹H-NMR (CDCl₃) δ: 2.37 (3H, s), 3.76 (2H, s), 3.82 (3H, s), 5.37 (2H,s), 6.92 (2H, t, J=8.2 Hz), 6.85-7.0 (1H, brs), 7.15-7.35 (6H, m), 7.42(2H, d, J=8.4 Hz), 7.57 (2H, d, J=8.4 Hz), 7.63 (1H, s).

Example 15 Production ofN-(4-(1-(2,6-difluorobenzyl)-3-(4-fluorophenyl)-5-((methyl(2-pyridinylmethyl)amino)methyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 4 by using the compoundobtained in Reference Example 17 (150 mg, 0.25 mmol) and2-chloromethylpyridine hydrochloride (85 mg, 0.52 mmol) gave the titlecompound (105 mg, 61%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 2.10 (3H, s), 3.71 (2H, s), 3.83 (3H, s), 3.97 (2H,s), 5.35 (2H, s), 6.93 (2H, t, J=8.2 Hz), 7.0-7.7 (14H, m), 8.4-8.5 (1H,m).

IR (KBr): 1723, 1665, 1532, 1510, 1474, 1236, 1032, 761 cm⁻¹.

Elemental analysis for C₃₅H₂₉F₃N₆O₄S.0.7H₂O

Calcd.: C, 60.11; H, 4.38; N, 12.02.

Found: C, 59.76; H, 4.03; N, 11.71.

mp 183-185° C.

Example 16 Production ofN-(4-(1-(2,6-difluorobenzyl)-3-(4-fluorophenyl)-5-((methyl(2-(2-pyridinyl)ethyl)amino)methyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 2 by using the compoundobtained in Reference Example 17 (150 mg, 0.25 mmol) and2-(2-hydroxyethyl)pyridine (0.19 g, 1.512 mmol) gave the title compound(100 mg, 57%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 2.19 (3H, s), 2.85 (4H, s), 3.82 (5H, s), 5.36 (2H,s), 6.9-7.55 (13H, m), 7.60 (1H, s), 8.4-8.45 (1H, m).

IR (KBr): 1723, 1665, 1534, 1510, 1474, 1464, 1238, 1034, 762 cm⁻¹.

Elemental analysis for C₃₆H₃₁F₃N₆O₄S.0.5H₂O

Calcd.: C, 60.92; H, 4.54; N, 11.84.

Found: C, 61.12; H, 4.63; N, 11.78.

mp 185-187° C.

Example 17 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-((methyl(2-(2-pyridinyl)ethyl)amino)methyl)-2,4-dioxo-3-(2-pyridinyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 2 by using the compoundobtained in Reference Example 14 (150 mg, 0.259 mmol) and2-(2-hydroxyethyl)pyridine (0.18 g, 1.425 mmol) gave the title compound(83 mg, 47%) as pale yellow crystals.

¹H-NMR (CDCl₃) δ: 2.21 (3H, s), 2.8-2.9 (4H, m), 3.82 (5H, s), 5.34 (2H,brs), 6.85-7.75 (13H, m), 7.60 (1H, s), 7.85-7.95 (1H, m), 8.4-8.5 (1H,m), 8.65-8.75 (1H, m).

IR (KBr): 1715, 1671, 1530, 1458, 1329, 1032, 781 cm⁻¹.

mp 194-196° C.

Example 18 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-((methyl(3-pyridinylmethyl)amino)methyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 4 by using the compoundobtained in Reference Example 15 (160 mg, 0.26 mmol) and3-chloromethylpyridine hydrochloride (85 mg, 0.52 mmol) gave the titlecompound (117 mg, 67%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 2.04 (3H, s), 3.58 (2H, s), 3.83 (3H, s), 3.92 (2H,s), 5.37 (2H, s), 6.92 (2H, t, J=8.2 Hz), 7.05-7.7 (14H, m), 8.35-8.45(2H, m).

IR (KBr): 1713, 1669, 1532, 1464, 1329, 1238, 1032, 787 cm⁻¹.

Elemental analysis for C₃₅H₃₀F₂N₆O₄S.0.3H₂O

Calcd.: C, 62.36; H, 4.58; N, 12.47.

Found: C, 62.22; H, 4.32; N, 12.57.

mp 184-185° C.

Example 19 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-((((6-(hydroxymethyl)-2-pyridinyl)methyl)(methyl)amino)methyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 4 by using the compoundobtained in Reference Example 15 (160 mg, 0.26 mmol) and6-bromomethyl-2-pyridinemethanol (106 mg, 0.52 mmol) gave the titlecompound (115 mg, 63%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 2.13 (3H, s), 3.72 (2H, s), 3.83 (3H, s), 3.97 (2H,s), 4.05-4.1 (1H, m), 4.65-4.75 (2H, m), 5.37 (2H, s), 6.93 (2H, t,J=8.2 Hz), 6.9-7.05 (1H, m), 7.1-7.2 (2H, m), 7.2-7.7 (12H, m).

IR (KBr): 1713, 1669, 1534, 1472, 1032, 789, 735 cm⁻¹.

Elemental analysis for C₃₆H₃₂F₂N₆O₅S.1.1H₂O

Calcd.: C, 60.17; H, 4.80; N, 11.70.

Found: C, 60.02; H, 4.70; N, 11.53.

Example 20 Production of methyl6-((((1-(2,6-difluorobenzyl)-6-(4-(((methoxyamino)carbonyl)amino)phenyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)methyl)(methyl)amino)methyl)nicotinate

The similar reaction as described in Example 4 by using the compoundobtained in Reference Example 15 (280 mg, 0.485 mmol) and methyl6-(bromomethyl)nicotinate (0.19 g, 0.825 mmol) gave the title compound(267 mg, 76%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 2.09 (3H, s), 3.76 (2H, s), 3.83 (3H, s), 3.93 (3H,s), 3.99 (2H, s), 5.35 (2H, s), 6.92 (2H, t, J=8.2 Hz), 7.26 (1H, s),7.2-7.6 (11H, m), 7.64 (1H, s), 8.05-8.15 (1H, m), 9.0-9.05 (1H, s).

IR (KBr): 1732, 1715, 1669, 1526, 1470, 1296, 1032, 789, 735 cm⁻¹.

Elemental analysis for C₃₇H₃₂F₂N₆O₆S

Calcd.: C, 61.15; H, 4.44; N, 11.56.

Found: C, 60.96; H, 4.47; N, 11.52.

Example 21 Production of6-((((1-(2,6-difluorobenzyl)-6-(4-(((methoxyamino)carbonyl)amino)phenyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)methyl)(methyl)amino)methyl)-N-methylnicotinamide

Ethyldiisopropylamine (0.48 ml, 2.76 mmol) and a solution ofdimethylaluminium chloride in hexane (0.98 M, 1.69 ml, 1.656 mmol) wereadded dropwise to a solution of methylamine (2M in THF) (1.38 ml, 2.76mmol) in dichloromethane (4 ml) under ice cooling, and the mixture wasstirred at room temperature for 30 minutes. A solution of the compoundobtained in Example 20 (200 mg, 0.275 mmol) in dichloromethane (14 ml)was added to the mixture, and the mixture was stirred at roomtemperature for 2 days. The reaction mixture was combined with anaqueous solution of sodium hydrogen carbonate and extracted withchloroform. The organic layer was washed with brine, dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by NH-silica gel column chromatography (Fuji SilysiaChemical) (eluent: ethyl acetate/methanol=40/1) and recrystallized fromdichloromethane/methanol/diethyl ether to give the title compound (68mg, 34%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 2.21 (3H, s), 3.00 (3H, d, J=4.6 Hz), 3.74 (2H, s),3.84 (3H, s), 3.92 (2H, s), 5.36 (2H, s), 6.5-6.65 (1H, m), 6.92 (2H, t,J=8.0 Hz), 7.15-7.6 (12H, m), 7.71 (1H, s), 7.9-8.0 (1H, m), 8.80-8.85(1H, m).

IR (KBr): 1713, 1665, 1534, 1470, 1327, 1032, 735 cm⁻¹.

Elemental analysis for C₃₇H₃₃F₂N₇O₅S.1.6H₂O

Calcd.: C, 58.89; H, 4.84; N, 12.99.

Found: C, 59.12; H, 5.06; N, 12.66.

Example 22 Production of ethyl6-((((1-(2,6-difluorobenzyl)-6-(4-(((methoxyamino)carbonyl)amino)phenyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)methyl)(methyl)amino)methyl)-2-pyridinecarboxylate

The similar reaction as described in Example 2 by using the compoundobtained in Reference Example 15 (578 mg, 1 mmol) and ethyl6-hydroxymethyl-2-pyridinecarboxylate (797 mg, 4.4 mmol) gave the titlecompound (590 mg, 80%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.40 (3H, t, J=7.2 Hz), 2.10 (3H, s), 3.79 (2H, s),3.83 (3H, s), 4.01 (2H, s), 4.43 (2H, q, J=7.2 Hz), 5.35 (2H, s), 6.92(2H, t, J=8.2 Hz), 7.15 (1H, s), 7.2-7.7 (13H, m), 7.88 (1H, d, J=7.4Hz).

IR (KBr): 1717, 1667, 1530, 1464, 1310, 1236, 1032, 747 cm⁻¹.

Elemental analysis for C₃₈H₃₄F₂N₆O₆S

Calcd.: C, 61.61; H, 4.63; N, 11.34.

Found: C, 61.39; H, 4.65; N, 11.17.

Example 23 Production of6-((((1-(2,6-difluorobenzyl)-6-(4-(((methoxyamino)carbonyl)amino)phenyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)methyl)(methyl)amino)methyl)-N-methyl-2-pyridinecarboxamide

The similar reaction as described in Example 21 by using the compoundobtained in Example 22 (300 mg, 0.413 mmol) and a solution ofmethylamine in THF (2 M, 2.07 ml, 4.13 mmol) gave the title compound(158 mg, 53%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 2.13 (3H, s), 2.95 (3H, d, J=5.2 Hz), 3.74 (2H, s),3.84 (3H, s), 3.99 (2H, s), 5.36 (2H, s), 6.93 (2H, t, J=8.2 Hz),7.15-7.7 (13H, m), 7.9-8.1 (3H, m).

IR (KBr): 1719, 1663, 1534, 1472, 1331, 1032, 737 cm⁻¹.

Elemental analysis for C₃₇H₃₃F₂N₇O₅S.1.0H₂O

Calcd.: C, 59.75; H, 4.74; N, 13.18.

Found: C, 59.60; H, 4.77; N, 13.12.

Example 24 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-(((2-(1H-imidazol-1-yl)ethyl)(methyl)amino)methyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The compound obtained in Reference Example 15 (289 mg, 0.5 mmol) wasdissolved in DMF (30 ml), and ethyldiisopropylamine (0.44 ml, 2.5 mmol)and 1-bromo-2-chloroethane (0.17 ml, 2.5 mmol) were added thereto. Thereaction mixture was stirred at 50-60° C. for 1 hour, combined with anaqueous solution of sodium hydrogen carbonate and extracted with ethylacetate. The combined organic layer was dried over magnesium sulfate andconcentrated under reduced pressure to give a halide. A solution of theobtained halide, imidazole (177 mg, 2.6 mmol) and potassium carbonate(72 mg, 0.52 mmol) in DMF (4 ml) was stirred at room temperature for 18hours and at 50-60° C. for 1 hour, combined with water and extractedwith ethyl acetate. The organic layer was washed with brine, dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by NH-silica gel column chromatography (Fuji SilysiaChemical) (eluent: ethyl acetate/methanol 80/1 to 20/1) andrecrystallized from dichloromethane/methanol/diethyl ether to give thetitle compound (40 mg, 23%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 2.17 (3H, s), 2.6-2.8 (2H, m), 3.80 (2H, s), 3.83 (3H,s), 3.9-4.0 (2H, m), 5.38 (2H, s), 6.78 (1H, s), 6.85-7.0 (3H, m),7.2-7.6 (12H, m), 7.71 (1H, s).

Example 25 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-(((2-(2-(2-hydroxyethyl)-1H-imidazol-1-yl)ethyl)(methyl)amino)methyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 24 by using the compoundobtained in Reference Example 15 (289 mg, 0.5 mmol) and2-(2-hydroxyethyl)imidazole (292 mg, 2.6 mmol) gave the title compound(19 mg, 10%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.9-2.1 (2H, m), 2.16 (3H, s), 2.6-2.8 (4H, m), 3.78(2H, s), 3.83 (2H, s), 3.9-4.0 (2H, m), 5.38 (2H, s), 6.70 (1H, s), 6.80(1H, s), 6.94 (2H, t, J=8.0 Hz), 7.2-7.6 (11H, m), 7.73 (1H, s).

Example 26 Production of2-(4-(1-(2,6-difluorobenzyl)-6-(4-(((methoxyamino)carbonyl)amino)phenyl)-5-((methyl(2-pyridinylmethyl)amino)methyl)-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)phenoxy)-N-methylacetamide

The similar reaction as described in Example 5 by using the compoundobtained in Reference Example 3 (320 mg, 0.5 mmol) and4-aminophenoxy-N-methylacetamide (135 mg, 0.75 mmol) gave the titlecompound (192 mg, 51%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 2.09 (3H, s), 2.93 (3H, d, J=4.8 Hz), 3.72 (2H, s),3.83 (3H, s), 3.97 (2H, s), 4.55 (2H, s), 5.35 (2H, s), 6.55-6.65 (1H,m), 6.92 (2H, t, J=8.0 Hz), 7.0-7.65 (14H, m), 8.44 (1H, d, J=6.0 Hz).

IR (KBr): 1721, 1669, 1532, 1472, 1236, 1032, 764 cm⁻¹.

Elemental analysis for C₃₈H₃₅F₂N₇O₆S.0.5H₂O

Calcd.: C, 59.68; H, 4.74; N, 12.82.

Found: C, 59.51; H, 4.66; N, 12.68.

Example 27 Production of2-(4-(1-(2,6-difluorobenzyl)-6-(4-(((methoxyamino)carbonyl)amino)phenyl)-5-((methyl(2-pyridinylmethyl)amino)methyl)-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)phenyl)-N-ethylacetamide

The similar reaction as described in Example 5 by using the compoundobtained in Reference Example 3 (320 mg, 0.5 mmol) and4-aminophenyl-N-ethylacetamide (134 mg, 0.75 mmol) gave the titlecompound (145 mg, 38%) as pale yellow crystals.

¹H-NMR (CDCl₃) δ: 1.10 (3H, t, J=7.2 Hz), 2.10 (3H, s), 3.2-3.4 (2H, m),3.64 (2H, s), 3.72 (2H, s), 3.83 (3H, s), 3.98 (2H, s), 5.36 (2H, s),5.45-5.55 (1H, m), 6.93 (2H, t, J=8.0 Hz), 7.0-7.1 (1H, m), 7.16 (1H,s), 7.25-7.7 (12H, m), 8.44 (1H, d, J=4.0 Hz).

IR (KBr): 1721, 1672, 1534, 1470, 1032, 762 cm⁻¹.

Elemental analysis for C₃₉H₃₇F₂N₇O₅S.0.5H₂O

Calcd.: C, 61.41; H, 5.02; N, 12.85.

Found: C, 61.44; H, 4.90; N, 12.75.

Example 28 Production of methyl3-(1-(2,6-difluorobenzyl)-6-(4-(((methoxyamino)carbonyl)amino)phenyl)-5-((methyl(2-pyridinylmethyl)amino)methyl)-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)propanate

The similar reaction as described in Example 5 by using the compoundobtained in Reference Example 3 (320 mg, 0.5 mmol) and 6-alanine methylester (115 mg, 0.75 mmol) gave the title compound (255 mg, 75%) as apale yellow amorphous compound.

¹H-NMR (CDCl₃) δ: 2.10 (3H, s), 2.65-2.8 (2H, m), 3.68 (3H, s), 3.72(2H, s), 3.83 (3H, s), 3.98 (2H, s), 4.3-4.5 (2H, m), 5.31 (2H, s), 6.91(2H, t, J=7.6 Hz), 7.0-7.4 (5H, m), 7.45-7.65 (5H, m), 8.4-8.5 (1H, m).

Example 29 Production of3-(1-(2,6-difluorobenzyl)-6-(4-(((methoxyamino)carbonyl)amino)phenyl)-5-((methyl(2-pyridinylmethyl)amino)methyl)-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)-N,N-dimethylpropanamide

The similar reaction as described in Example 21 by using the compoundobtained in Example 28 (300 mg, 0.413 mmol) and a solution ofdimethylamine in THF (2M) (1.63 ml, 3.26 mmol) gave the title compound(73 mg, 33%) as pale yellow powders.

¹H-NMR (CDCl₃) δ: 2.09 (3H, s), 2.75 (3H, d, J=7.8 Hz), 2.94 (3H, s),3.02 (3H, s), 3.73 (2H, s), 3.83 (3H, s), 4.07 (2H, s), 4.40 (2H, t,J=7.8 Hz), 5.33 (2H, s), 6.91 (2H, t, J=8.2 Hz), 7.0-7.35 (5H, m),7.5-7.65 (5H, m), 8.45 (1H, d, J=4.0 Hz).

IR (KBr): 1703, 1659, 1530, 1472, 1321, 1034, 779 cm⁻¹.

Elemental analysis for C₃₄H₃₅F₂N₇O₅S.1.0H₂O

Calcd.: C, 57.54; H, 5.25; N, 13.81.

Found: C, 57.56; H, 5.05; N, 13.59.

Example 30 Production ofN-(4-(1-(2,6-difluorobenzyl)-3-(4-hydroxycyclohexyl)-5-((methyl(2-pyridinylmethyl)amino)methyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 5 by using the compoundobtained in Example 28 (320 mg, 0.5 mmol) and 4-aminohexanol (86 mg,0.75 mmol) gave the title compound (154 mg, 45%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.4-1.8 (4H, m), 2.0-2.1 (2H, m), 2.12 (3H, s),2.55-2.75 (2H, m), 3.73 (2H, s), 3.7-3.8 (1H, m), 3.82 (3H, s), 3.98(2H, s), 4.9-5.1 (1H, brm), 5.29 (2H, s), 6.91 (2H, t, J=8.2 Hz),7.0-7.4 (7H, m), 7.45-7.65 (5H, m), 8.45 (1H, d, J=4.8 Hz).

IR (KBr): 1705, 1659, 1530, 1470, 1312, 1236, 1069, 1034, 783 cm⁻¹.

Elemental analysis for C₃₅H₃₆F₂N₆O₅S.1.5H₂O

Calcd.: C, 58.57; H, 5.48; N, 11.71.

Found: C, 58.65; H, 5.35; N, 11.64.

Example 31 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-((methyl(2-(2H-tetrazol-2-yl)ethyl)aminomethyl))-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea(1)

Production ofN-(4-(1-(2,6-difluorobenzyl)-5-((methyl(2-(1H-tetrazol-1-yl)ethyl)amino)methyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea(2)

Potassium carbonate (2.075 g, 15 mmol) was added to a solution oftetrazole (0.70 g, 10 mmol) and 1-bromo-2-chloroethane (1.25 ml, 15mmol) in DMF (5 ml), and the mixture was stirred at room temperature for16 hours. The reaction mixture was combined with saturated brine andextracted twice with ethyl acetate. The combined extract was dried overmagnesium sulfate and concentrated under reduced pressure to give ahalide (4.23 g including DMF).

N,N-diisopropylethylamine (1.16 ml, 6.67 mmol) and the halide obtainedabove were added to a solution of the compound obtained in ReferenceExample 15 (578 mg, 1 mmol) in DMF (10 ml), and the mixture was stirredat 60-70° C. for 16 hours. The reaction mixture was combined with anaqueous solution of sodium hydrogen carbonate and extracted with ethylacetate. The organic layer was washed with brine, dried over magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: ethylacetate/hexane=9/1) and recrystallized fromdichloromethane/methanol/diethyl ether to give the title compound 2-ylform (80 mg, 12%) and 1-yl form (38 mg, 57%) as colorless crystals.

2-yl form (1)

¹H-NMR (CDCl₃) δ: 2.25 (3H, s), 3.04 (2H, t, J=6.2 Hz), 3.78 (2H, s),3.83 (3H, s), 4.66 (2H, t, J=6.2 Hz), 5.38 (2H, s), 6.94 (2H, t, J=8.0Hz), 7.16 (1H, s), 7.2-7.6 (10H, m), 7.64 (1H, s), 8.30 (1H, s).

IR (KBr): 1713, 1669, 1530, 1470, 1325, 1032, 735 cm⁻¹.

Elemental analysis for C₃₂H₂₉F₂N₉O₄S.0.5H₂O

Calcd.: C, 56.30; H, 4.43; N, 18.46.

Found: C, 56.18; H, 4.42; N, 18.19.

1-yl form (2)

¹H-NMR (CDCl₃) δ: 2.02 (3H, s), 2.7-2.8 (2H, m), 3.78 (2H, s), 3.83 (3H,s), 4.4-4.5 (2H, m), 5.38 (2H, s), 6.92 (2H, t, J=8.0 Hz), 7.17 (1H, s),7.25-7.65 (10H, m), 7.66 (1H, s).

IR (KBr): 1713, 1669, 1530, 1470, 1327, 1236, 1032, 735 cm⁻¹.

Elemental analysis for C₃₂H₂₉F₂N₉O₄S.0.5H₂O

Calcd.: C, 56.30; H, 4.43; N, 18.46.

Found: C, 56.54; H, 4.30; N, 18.27.

Example 32 Production ofN-(4-(1-(2,6-difluorobenzyl)-3-(2-hydroxyethyl)-5-((methyl(2-pyridinylmethyl)amino)methyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 5 by using the compoundobtained in Reference Example 3 (410 mg, 0.64 mmol) and 2-aminoethanol(0.06 ml, 0.96 mmol) gave the title compound (76 mg, 19%) as colorlesscrystals.

¹H-NMR (CDCl₃) δ: 2.22 (3H, s), 3.3-3.5 (1H, br), 3.78 (2H, s), 3.83(3H, s), 3.9-4.05 (2H, m), 3.99 (2H, s), 4.35-4.4 (2H, m), 5.27 (2H, s),6.91 (2H, t, J=8.0 Hz), 6.9-7.1 (1H, m), 7.15 (1H, s), 7.2-7.65 (8H, m),8.35-8.4 (1H, m).

IR (KBr): 1709, 1649, 1470, 1323, 1030, 787 cm⁻¹.

Elemental analysis for C₃₁H₃₀F₂N₆O₅S.0.5H₂O

Calcd.: C, 57.67; H, 4.84; N, 13.02.

Found: C, 57.77; H, 4.90; N, 12.82.

Example 33 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-((methyl(3-(2-oxo-1-pyrrolidinyl)propyl)amino)methyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 2 by using the compoundobtained in Reference Example 15 (404 mg, 0.7 mmol) and1-(3-hydroxypropyl)-2-pyrrolidone (0.55 g, 3.85 mmol) gave the titlecompound (322 mg, 66%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.5-1.7 (2H, m), 1.8-2.0 (2H, m), 2.05 (3H, s),2.25-2.45 (4H, m), 3.15 (2H, t, J=7.8 Hz), 3.23 (2H, t, J=7.2 Hz), 3.76(2H, s), 3.83 (3H, s), 5.37 (2H, s), 6.93 (2H, t, J=8.0 Hz), 7.15 (1H,s), 7.2-7.6 (10H, m), 7.67 (1H, s).

IR (KBr): 1715, 1671, 1532, 1470, 1327, 1032, 735 cm⁻¹.

Elemental analysis for C₃₆H₃₆F₂N₆O₅S.1.0H₂O

Calcd.: C, 59.99; H, 5.31; N, 11.66.

Found: C, 60.21; H, 5.18; N, 11.74.

mp 128-129° C.

Example 34 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-((methyl(2-(2-oxo-1-pyrrolidinyl)ethyl)amino)methyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 2 by using the compoundobtained in Reference Example 15 (404 mg, 0.7 mmol) and1-(3-hydroxyethyl)-2-pyrrolidone (0.50 g, 3.85 mmol) gave the titlecompound (290 mg, 60%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.7-1.85 (2H, m), 2.14 (3H, s), 2.21 (2H, t, J=8.1Hz), 2.54 (2H, t, J=6.2 Hz), 3.19 (2H, t, J=7.0 Hz), 3.29 (2H, t, J=6.2Hz), 3.77 (2H, s), 3.83 (3H, s), 5.38 (2H, s), 6.93 (2H, t, J=8.1 Hz),7.18 (1H, s), 7.25-7.7 (11H, m).

IR (KBr): 1715, 1672, 1530, 1470, 1323, 1238, 1032, 735 cm⁻¹.

Elemental analysis for C₃₅H₃₄F₂N₆O₅S.0.5H₂O

Calcd.: C, 60.25; H, 5.06; N, 12.04.

Found: C, 60.29; H, 5.04; N, 12.13.

mp 134-136° C.

Example 35 Production ofN-(4-(1-(2,6-difluorobenzyl)-3-(4-fluorophenyl)-5-((methyl-(2-(2-oxo-1-pyrrolidinyl)ethyl)amino)methyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 2 by using the compoundobtained in Reference Example 17 (350 mg, 0.588 mmol) and1-(3-hydroxyethyl)-2-pyrrolidone (0.50 g, 3.85 mmol) gave the titlecompound (283 mg, 68%) as pale yellow crystals.

¹H-NMR (CDCl₃) δ: 1.7-1.9 (2H, m), 2.15 (3H, s), 2.15-2.3 (2H, m), 2.52(2H, t, J=6.2 Hz), 3.20 (2H, t, J=6.8 Hz), 3.29 (2H, t, J=6.2 Hz), 3.77(2H, s), 3.83 (3H, s), 5.37 (2H, s), 6.93 (2H, t, J=8.2 Hz), 7.1-7.35(6H, m), 7.5-7.65 (4H, m), 7.64 (1H, s).

IR (KBr): 1723, 1667, 1532, 1472, 1236, 1034, 837, 762 cm⁻¹.

Elemental analysis for C₃₅H₃₃F₃N₆O₅S.0.5H₂O

Calcd.: C, 58.73; H, 4.79; N, 11.74.

Found: C, 58.99; H, 4.98; N, 11.92.

mp 198-200° C.

Example 36 Production ofN-(2-(((1-(2,6-difluorobenzyl)-3-(4-fluorophenyl)-6-(4-(((methoxyamino)carbonyl)amino)phenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)methyl)(methyl)amino)ethyl)-N-methylmethanesulfonamide

The similar reaction as described in Example 2 by using the compoundobtained in Reference Example 17 (350 mg, 0.588 mmol) and2-methylaminoethanol (0.29 g, 3.85 mmol) gave the title compound (263mg, 61%) as pale yellow crystals.

¹H-NMR (CDCl₃) δ: 2.13 (3H, s), 2.55 (2H, t, J=6.4 Hz), 2.70 (3H, s),2.71 (3H, s), 3.15 (2H, t, J=6.4 Hz), 3.81 (2H, s), 3.83 (3H, s), 5.37(2H, s), 6.93 (2H, t, J=8.2 Hz), 7.1-7.7 (11H, m).

IR (KBr): 1725, 1663, 1534, 1474, 1331, 1236, 1142, 1034, 793 cm⁻¹.

Elemental analysis for C₃₃H₃₃F₃N₆O₆S₂

Calcd.: C, 54.24; H, 4.55; N, 11.50.

Found: C, 54.10; H, 4.45; N, 11.36.

mp 218-220° C.

Example 37 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-((methyl(((2S)-1-(methylsulfonyl)-2-pyrrolidinyl)methyl)amino)methyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 2 by using the compoundobtained in Reference Example 15 (404 mg, 0.7 mmol) and(L)-2-hydroxymethylpyrrolidine (0.39 g, 3.85 mmol) gave the titlecompound (262 mg, 51%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.7-1.85 (4H, m), 2.08 (3H, s), 2.2-2.4 (1H, m),2.5-2.65 (1H, m), 2.72 (3H, s), 3.15-3.3 (2H, m), 3.7-3.9 (3H, m), 3.83(3H, s), 5.37 (2H, s), 6.92 (2H, t, J=8.2 Hz), 7.13 (1H, s), 7.2-7.7(11H, m).

IR (KBr): 1713, 1667, 1528, 1470, 1333, 1148, 1030, 785 cm⁻¹.

Elemental analysis for C₃₅H₃₆F₂N₆O₆S₂

Calcd.: C, 56.90; H, 4.91; N, 11.37.

Found: C, 56.55; H, 4.87; N, 11.23.

mp 195-197° C.

Example 38 Production ofN-(4-(1-(2,6-difluorobenzyl)-3-(4-fluorophenyl)-5-((methyl(((2S)-1-(methylsulfonyl)-2-pyrrolidinyl)methyl)amino)methyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 2 by using the compoundobtained in Reference Example 17 (400 mg, 0.672 mmol) and(L)-2-hydroxymethylpyrrolidine (0.39 g, 3.85 mmol) gave the titlecompound (222 mg, 44%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.7-1.85 (4H, m), 2.09 (3H, s), 2.25-2.35 (1H, m),2.55-2.65 (1H, m), 2.71 (3H, s), 3.15-3.3 (2H, m), 3.65-3.7 (2H, m),3.74 (1H, d, J=12.0 Hz), 3.83 (3H, s), 3.87 (1H, d, J=12.0 Hz), 5.36(2H, s), 6.92 (2H, t, J=8.2 Hz), 6.85-6.95 (1H, m), 7.1-7.35 (5H, m),7.49 (2H, d, J=8.4 Hz), 7.55 (2H, d, J=8.4 Hz), 7.62 (1H, s).

IR (KBr): 1715, 1667, 1530, 1470, 1333, 1236, 1152, 1032, 795 cm⁻¹.

Elemental analysis for C₃₅H₃₅F₃N₆O₆S₂

Calcd.: C, 55.55; H, 4.66; N, 11.10.

Found: C, 55.42; H, 4.45; N, 11.01.

mp 202-204° C.

Example 39 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-((methyl(((2R)-1-(methylsulfonyl)-2-pyrrolidinyl)methyl)amino)methyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 2 by using the compoundobtained in Reference Example 15 (188 mg, 0.325 mmol) and(R)-2-hydroxymethylpyrrolidine (0.14 g, 1.38 mmol) gave the titlecompound (136 mg, 57%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.7-1.85 (4H, m), 2.08 (3H, s), 2.2-2.4 (1H, m),2.5-2.65 (1H, m), 2.72 (3H, s), 3.15-3.3 (2H, m), 3.7-3.9 (3H, m), 3.83(3H, s), 5.37 (2H, s), 6.92 (2H, t, J=8.2 Hz), 7.13 (1H, s), 7.2-7.7(11H, m).

IR (KBr): 1713, 1665, 1530, 1470, 1333, 1148, 1030, 785 cm⁻¹.

Elemental analysis for C₃₅H₃₆F₂N₆O₆S₂.0.5H₂O

Calcd.: C, 56.21; H, 4.99; N, 11.24.

Found: C, 56.29; H, 4.79; N, 11.11.

mp 208-210° C.

Example 40 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-3-(2-pyridinyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

Diethyl cyanophosphate (245 mg) and N-ethyldiisopropylamine (284 μl)were added to a solution of the compound obtained in Reference Example 7(607 mg) and 2-aminopyridine (142 mg) in DMF (10 ml) under ice cooling,and the reaction mixture was warmed gradually to room temperature andstirred for 13 hours. The reaction mixture was distributed between ethylacetate and water. The organic layer was successively washed with waterand saturated brine, dried over magnesium sulfate, and concentratedunder reduced pressure. The obtained residue was roughly purified byaminopropyl silica gel column chromatography (Fuji Silysia Chemical).The obtained crude amide (350 mg) was dissolved in ethanol (25.5 ml),and a solution of 28% sodium methoxide in methanol (196 mg) was addedthereto. The mixture was stirred at room temperature for 15 hours. Thereaction mixture was neutralized with 1N hydrochloric acid (1 ml), andthe solvent was distilled off. The residue was distributed between ethylacetate and water. The organic layer was successively washed with waterand saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure. The obtained residuewas purified by aminopropyl silica gel column chromatography (45 g,eluent: ethyl acetate/hexane 7/3 to ethyl acetate) and recrystallizedfrom THF-ethanol to give the title compound (210 mg) as colorlesscrystals.

Elemental analysis for C₃₁H₃₀N₆O₅SF₂

Calcd.: C, 58.48; H, 4.75; N, 13.20.

Found: C, 58.46; H, 4.68; N, 12.93.

¹H-NMR (CDCl₃) δ: 2.15 (3H, s), 2.62 (2H, t, J=5.9 Hz), 3.26 (3H, s),3.41 (2H, t, J=5.9 Hz), 3.80 (3H, s), 3.81 (2H, brs), 5.34 (2H, brs),6.91 (2H, t, J=8.1 Hz), 7.24-7.40 (4H, m), 7.53 (2H, d, J=8.4 Hz), 7.62(2H, d, J=8.4 Hz), 7.65 (1H, s), 7.88 (1H, dt, J=1.5 Hz, 7.8 Hz),8.67-8.69 (1H, m).

IR (KBr): 1717, 1674, 1591, 1530, 1460, 1329 cm⁻¹.

Example 41 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-(((2-ethoxyethyl)(methyl)amino)methyl)-2,4-dioxo-3-(2-pyridinyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

To a solution of the compound obtained in Reference Example 14 (251 mg)in DMF (4.3 ml) were added 2-ethoxyethyl chloride (141 mg),N-ethyldiisopropylamine (245 μl) and potassium iodide (107 mg), and themixture was stirred at 60° C. for 24 hours. The reaction mixture wasdistributed between ethyl acetate and water. The organic layer waswashed with saturated brine and dried over magnesium sulfate. Thesolvent was distilled off, and the residue was purified by aminopropylsilica gel column chromatography (Fuji Silysia Chemical) (45 g, eluent:ethyl acetate/hexane=3/2 to 4/1) and recrystallized from ethyl acetateto give the title compound (62 mg) as colorless crystals.

Elemental analysis for C₃₂H₃₂N₆O₅SF₂.0.1AcOEt

Calcd.: C, 59.01; H, 5.01; N, 12.74.

Found: C, 59.11; H, 5.13; N, 12.55.

¹H-NMR (CDCl₃) δ: 1.13 (3H, t, J=6.9 Hz), 2.15 (3H, s), 2.63 (2H, t,J=6.2 Hz), 3.39 (2H, q, J=6.9 Hz), 3.44 (2H, t, J=6.2 Hz), 3.80 (2H,brs), 3.81 (3H, s), 5.34 (2H, brs), 6.91 (2H, t, J=8.1 Hz), 7.19 (1H,s), 7.27-7.32 (1H, m), 7.35-7.41 (2H, m), 7.53 (2H, d, J=8.4 Hz), 7.63(1H, s), 7.64 (2H, d, J=8.4 Hz), 7.88 (1H, dt, J=1.2 Hz, 7.5 Hz), 8.68(1H, dt, J=0.9 Hz, 4.8 Hz).

IR (KBr): 1717, 1674, 1591, 1530, 1460, 1329 cm⁻¹.

Example 42 Production ofN-(4-(1-(2,6-difluorobenzyl)-3-(5-fluoro-2-pyridinyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

By a similar manner to Example 40, a crude amide (270 mg) was obtainedfrom the compound obtained in Reference Example 7 (304 mg), diethylcyanophosphate (153 μl), 2-amino-5-fluoropyridine (113 mg) andN-ethyldiisopropylamine (190 μl), and the title compound (113 mg) wasobtained from the crude amide by using methanol (19 ml) and a solutionof 28% sodium methoxide in methanol (146 mg).

Elemental analysis for C₃₁H₂₉N₆O₅SF₃

Calcd.: C, 56.87; H, 4.46; N, 12.84.

Found: C, 56.69; H, 4.57; N, 12.83.

¹H-NMR (CDCl₃) δ: 2.13 (3H, s), 2.62 (2H, t, J=5.9 Hz), 3.26 (3H, s),3.41 (2H, t, J=5.9 Hz), 3.80 (2H, brs), 3.82 (3H, s), 5.33 (2H, brs),6.92 (2H, t, J=8.3 Hz), 7.19 (1H, s), 7.28-7.38 (2H, m), 7.52-7.63 (6H,m), 8.51 (1H, d, J=3.0 Hz).

IR (KBr): 1715, 1674, 1586, 1530, 1462 cm⁻¹.

Example 43 Production ofN-(4-(3-(5-bromo-2-pyridinyl)-1-(2,6-difluorobenzyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 40 by using the compoundobtained in Reference Example 7 (304 mg), diethyl cyanophosphate (153μl), 2-amino-5-bromopyridine (173 mg) and N-ethyldiisopropylamine (190μl) gave a crude amide (228 mg).

Furthermore, the similar reaction by using methanol (14.5 ml) and asolution of 28% sodium methoxide in methanol (112 mg) gave the titlecompound (113 mg).

Elemental analysis for C₃₁H₂₉N₆O₅SBrF₂.0.5H₂O

Calcd.: C, 51.39; H, 4.17; N, 11.60.

Found: C, 51.68; H, 4.25; N, 11.53.

¹H-NMR (CDCl₃) δ: 2.13 (3H, s), 2.62 (2H, t, J=5.9 Hz), 3.26 (3H, s),3.41 (2H, t, J=5.9 Hz), 3.78 (2H, brs), 3.80 (3H, s), 5.32 (2H, brs),6.92 (2H, t, J=8.1 Hz), 7.27 (1H, d, J=8.4 Hz), 7.27-7.33 (1H, m), 7.37(1H, s), 7.54 (2H, d, J=9.0 Hz), 7.60 (2H, d, J=9.0 Hz), 7.64 (1H, s),7.98 (1H, dd, J=2.7 Hz, 8.4 Hz), 8.72 (1H, d, J=2.7 Hz).

IR (KBr): 2938, 1717, 1674, 1590, 1456 cm⁻¹.

Example 44 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-3-(5-methyl-2-pyridinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 40 by using the compoundobtained in Reference Example 7 (304 mg), diethyl cyanophosphate (153μl), 2-amino-5-methylpyridine (109 mg) and N-ethyldiisopropylamine (190μl) gave a crude amide (188 mg). Furthermore, the similar reaction byusing methanol (13.5 ml), a solution of 28% sodium methoxide in methanol(103 mg) gave the title compound (122 mg).

Elemental analysis for C₃₂H₃₂N₆O₅SF₂.0.5H₂O

Calcd.: C, 58.26; H, 5.04; N, 12.74.

Found: C, 58.55; H, 5.14; N, 12.67.

¹H-NMR (CDCl₃) δ: 2.14 (3H, s), 2.39 (3H, s), 2.62 (2H, t, J=5.7 Hz),3.26 (3H, s), 3.41 (2H, t, J=5.7 Hz), 3.77 (2H, brs), 3.80 (3H, s), 5.26(1H, brs), 5.38 (1H, brs), 6.91 (2H, t, J=8.3 Hz), 7.23-7.34 (2H, m),7.42 (1H, s), 7.53 (2H, d, J=8.7 Hz), 7.62 (2H, d, J=8.7 Hz), 7.66 (1H,s), 7.66-7.69 (1H, m), 8.48 (1H, d, J=2.4 Hz).

IR (KBr): 2938, 1717, 1675, 1586, 1530, 1462 cm⁻¹.

Example 45 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-3-(6-methyl-2-pyridinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 40 by using the compoundobtained in Reference Example 7 (423 mg), diethyl cyanophosphate (212μl), 2-amino-6-methylpyridine (151 mg) and N-ethyldiisopropylamine (265μl) gave a crude amide (242 mg). Furthermore, the similar reaction byusing methanol (17 ml), a solution of 28% sodium methoxide in methanol(131 mg) gave the title compound (145 mg).

Elemental analysis for C₃₂H₃₂N₆O₅SF₂.0.5H₂O

Calcd.: C, 58.26; H, 5.04; N, 12.74.

Found: C, 58.39; H, 4.86; N, 12.79.

¹H-NMR (CDCl₃) δ: 2.15 (3H, s), 2.60 (3H, s), 2.62 (2H, t, J=5.8 Hz),3.27 (3H, s), 3.41 (2H, t, J=5.8 Hz), 3.66-3.94 (2H, m), 3.81 (3H, s),5.15 (1H, d, J=15.3 Hz), 5.48 (1H, d, J=15.3 Hz), 6.91 (2H, t, J=8.1Hz), 7.16 (1H, d, J=7.8 Hz), 7.21 (1H, d, J=7.8 Hz), 7.25 (1H, s),7.26-7.35 (1H, m), 7.53 (2H, d, J=8.7 Hz), 7.63 (1H, s), 7.53 (2H, d,J=8.7 Hz), 7.64 (2H, d, J=8.7 Hz), 7.76 (1H, t, J=7.8 Hz).

IR (KBr): 2936, 1715, 1672, 1603, 1530, 1472 cm⁻¹.

Example 46 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-3-(3-methoxy-6-methyl-2-pyridinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 40 by using the compoundobtained in Reference Example 7 (455 mg), diethyl cyanophosphate (227μl), 2-amino-3-methoxy-6-methylpyridine (208 mg) andN-ethyldiisopropylamine (310 μl) gave a crude amide (130 mg).Furthermore, the similar reaction by using methanol (8.5 ml), a solutionof 28% sodium methoxide in methanol (666 mg) gave the title compound(107 mg).

Elemental analysis for C₃₃H₃₄N₆O₆SF₂.0.5H₂O

Calcd.: C, 57.47; H, 5.11; N, 12.18.

Found: C, 57.54; H, 5.03; N, 12.26.

¹H-NMR (CDCl₃) δ: 2.13 (3H, s), 2.51 (3H, s), 2.62 (2H, t, J=5.9 Hz),3.26 (3H, s), 3.40 (2H, t, J=5.9 Hz), 3.77 (1H, d, J=12.3 Hz), 3.77 (3H,s), 3.79 (3H, s), 3.86 (1H, d, J=12.3 Hz), 5.24 (1H, d, J=15.6 Hz), 5.40(1H, d, J=15.6 Hz), 6.90 (2H, t, J=8.1 Hz), 7.19 (1H, d, J=8.4 Hz),7.23-7.34 (1H, m), 7.27 (1H, d, J=8.4 Hz), 7.51 (2H, d, J=8.7 Hz), 7.58(2H, d, J=8.7 Hz), 7.65 (1H, s), 7.69 (1H, s).

IR (KBr): 2938, 1715, 1674, 1589, 1532, 1470 cm⁻¹.

Example 47 Production ofN-(4-(1-(2,6-difluorobenzyl)-3-(3-hydroxy-6-methyl-2-pyridinyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

A crude amide (163 mg) was produced by reacting the compound obtained inReference Example 7 (455 mg) with1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (306 mg),1-hydroxybenzotriazole (288 mg), 2-amino-3-hydroxy-6-methylpyridine (187mg) and N-ethyldiisopropylamine (517 μl). Furthermore, the titlecompound (127 mg) was obtained from the crude amide by using methanol(11 ml) and a solution of 28% sodium methoxide in methanol (85 mg).

Elemental analysis for C₃₃H₃₄N₆O₆SF₂H₂O

Calcd.: C, 56.13; H, 5.01; N, 12.27.

Found: C, 56.03; H, 5.21; N, 12.05.

¹H-NMR (CDCl₃) δ: 2.11 (3H, s), 2.48 (3H, s), 2.51-2.59 (2H, m), 3.20(3H, s), 3.30-3.46 (4H, m), 3.60 (1H, d, J=12.3 Hz), 3.79 (3H, s), 4.05(1H, d, J=12.3 Hz), 5.21 (1H, d, J=15.6 Hz), 5.31 (1H, d, J=15.6 Hz),6.88 (2H, t, J=8.1 Hz), 7.07 (1H, d, J=8.1 Hz), 7.21-7.31 (2H, m),7.43-7.51 (4H, m), 7.69 (1H, s).

IR (KBr): 2936, 1715, 1669, 1591, 1530, 1472 cm⁻¹.

Example 48 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-3-(3-methoxy-2-pyridinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 40 by using the compoundobtained in Reference Example 7 (455 mg), diethyl cyanophosphate (285μl), 2-amino-3-methoxypyridine (233 mg) and N-ethyldiisopropylamine (388μl) gave a crude amide (226 mg). Furthermore, the similar reaction byusing methanol (15.5 ml), a solution of 28% sodium methoxide in methanol(120 mg) gave the title compound (115 mg).

Elemental analysis for C₃₂H₃₂N₆O₆SF₂.0.5H₂O

Calcd.: C, 56.88; H, 4.92; N, 12.44.

Found: C, 56.88; H, 4.96; N, 12.31.

¹H-NMR (CDCl₃) δ: 2.20 (3H, s), 2.63 (2H, t, J=6.2 Hz), 3.28 (3H, s),3.41 (2H, t, J=6.2 Hz), 3.78 (1H, d, J=12.3 Hz), 3.82 (3H, s), 3.84 (3H,s), 3.88 (1H, d, J=12.3 Hz), 5.35 (2H, s), 6.92 (2H, t, J=8.1 Hz), 7.17(1H, s), 7.23-7.39 (3H, m), 7.54 (2H, d, J=8.8 Hz), 7.57 (1H, s), 7.69(2H, d, J=8.8 Hz), 8.23-8.27 (1H, m).

IR (KBr): 1717, 1674, 1590, 1530, 1470 cm⁻¹.

Example 49 Production ofN-(4-(1-(2,6-difluorobenzyl)-3-(4-(1-hydroxy-1-methylethyl)phenyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 40 by using the compoundobtained in Reference Example 7 (1.22 g), diethyl cyanophosphate (456μl), 4-(1-hydroxy-1-methylethyl)aniline (454 mg) andN-ethyldiisopropylamine (569 μl) gave a crude amide (1.12 g).Furthermore, the similar reaction by using ethanol (60 ml), a solutionof 28% sodium methoxide in methanol (579 mg) gave the title compound(849 mg).

Elemental analysis for C₃₅H₃₇N₅O₆SF₂.0.5H₂O

Calcd.: C, 59.82; H, 5.45; N, 9.97.

Found: C, 60.09; H, 5.40; N, 10.06.

¹H-NMR (CDCl₃) δ: 1.60 (6H, s), 1.79 (1H, s), 2.14 (3H, s), 2.63 (2H, t,J=5.9 Hz), 3.27 (3H, s), 3.41 (2H, t, J=5.9 Hz), 3.81 (3H, s), 3.82 (2H,s), 5.36 (2H, s), 6.92 (2H, t, J=8.3 Hz), 7.20-7.34 (4H, m), 7.53 (2H,d, J=8.7 Hz), 7.60-7.63 (5H, m).

IR (KBr): 1713, 1669, 1590, 1532, 1470 cm⁻¹.

Example 50 Production ofN-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-3-(4-(1-hydroxy-1-methylethyl)phenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 40 by using4-(N-benzyl-N-methylaminomethyl)-2-[N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino]-5-[4-(3-methoxyureido)phenyl]thiophene-3-carboxylicacid (470 mg), diethyl cyanophosphate (167 μl),4-(1-hydroxy-1-methylethyl)aniline (166 mg) and N-ethyldiisopropylamine(209 μl) gave a crude amide (422 mg). Furthermore, the similar reactionby using ethanol (25.5 ml) and sodium ethoxide (70 mg) gave the titlecompound (113 mg).

Elemental analysis for C₃₉H₃₇N₅O₅SF₂

Calcd.: C, 64.54; H, 5.14; N, 9.65.

Found: C, 64.46; H, 5.05; N, 9.70.

¹H-NMR (CDCl₃) δ: 1.62 (6H, s), 1.77 (1H, s), 2.05 (3H, s), 3.56 (2H,s), 3.82 (3H, s), 3.90 (2H, s), 5.36 (2H, s), 6.91 (2H, t, J=8.1 Hz),7.14-7.38 (9H, m), 7.55 (2H, d, J=9.0 Hz), 7.62 (1H, s), 7.64 (2H, d,J=8.7 Hz), 7.72 (2H, d, J=8.4 Hz).

IR (KBr): 1713, 1669, 1590, 1530, 1470 cm⁻¹.

Example 51 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-3-(4-(1-methoxy-1-methylethyl)phenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 40 by using the compoundobtained in Reference Example 7 (364 mg), diethyl cyanophosphate (136μl), 4-(1-methoxy-1-methylethyl)aniline (149 mg) andN-ethyldiisopropylamine (171 μl) gave a crude amide (292 mg).Furthermore, the similar reaction by using ethanol (19 ml) and asolution of 28% sodium methoxide in methanol (146 mg) gave the titlecompound (146 mg).

Elemental analysis for C₃₆H₃₉N₅O₆SF₂

Calcd.: C, 61.09; H, 5.55; N, 9.89.

Found: C, 60.97; H, 5.54; N, 9.92.

¹H-NMR (CDCl₃) δ: 1.55 (6H, s), 2.15 (3H, s), 2.64 (2H, t, J=5.9 Hz),3.11 (3H, s), 3.27 (3H, s), 3.41 (2H, t, J=5.9 Hz), 3.82 (3H, s), 3.83(2H, s), 5.36 (2H, s), 6.92 (2H, t, J=8.3 Hz), 7.16 (1H, s), 7.24-7.36(4H, m), 7.51-7.63 (6H, m).

IR (KBr): 1715, 1674, 1590, 1532, 1464, 1327 cm⁻¹.

Example 52 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-3-(1-methyl-1H-imidazol-2-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 40 by using the compoundobtained in Reference Example 7 (455 mg), diethyl cyanophosphate (228μl), 2-amino-1-methyl-1H-imidazole hydrochloride (214 mg) andN-ethyldiisopropylamine (586 μl) gave a crude amide (48 mg).Furthermore, the similar reaction by using methanol (3.3 ml) and asolution of 28% sodium methoxide in methanol (25 mg) gave the titlecompound (17 mg).

¹H-NMR (CDCl₃) δ: 2.15 (3H, s), 2.61 (2H, dt, J=1.8 Hz, 6.90 Hz), 3.27(3H, s), 3.40 (2H, dt, J=1.8 Hz, 6.0 Hz), 3.53 (3H, s), 3.75 (1H, d,J=12.3 Hz), 3.80 (3H, s), 3.81 (1H, d, J=12.3 Hz), 5.12 (1H, d, J=15.9Hz), 5.57 (1H, d, J=15.9 Hz), 6.91 (2H, t, J=8.1 Hz), 6.99 (1H, d, J=1.5Hz), 7.14 (1H, d, J=1.5 Hz), 7.28 (1H, s), 7.25-7.34 (1H, m), 7.53 (2H,d, J=9.0 Hz), 7.60 (2H, d, J=9.0 Hz), 7.70 (1H, s).

IR (KBr): 1725, 1682, 1590, 1530, 1470 cm⁻¹.

Example 53 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-3-(3-methylbutyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 40 by using the compoundobtained in Reference Example 7 (455 mg), diethyl cyanophosphate (228μl), isoamylamine (139 mg) and N-ethyldiisopropylamine (310 μl) gave acrude amide (102 mg).

Furthermore, the stirring with methanol (7 ml), a solution of 28% sodiummethoxide in methanol (55 mg) at 55° C. for 20 hours and the similartreatment gave the title compound (80 mg).

Elemental analysis for C₃₁H₃₇N₅O₅SF₂

Calcd.: C, 59.13; H, 5.92; N, 11.12.

Found: C, 58.97; H, 5.99; N, 10.90.

¹H-NMR (CDCl₃) δ: 0.98 (6H, d, J=6.3 Hz), 1.52-1.58 (2H, m), 1.64-1.71(1H, m), 2.14 (3H, s), 2.66 (2H, t, J=5.9 Hz), 3.30 (3H, s), 3.45 (2H,t, J=5.9 Hz), 3.81 (3H, s), 3.85 (2H, s), 4.04-4.09 (2H, m), 5.33 (2H,s), 6.90 (2H, t, J=8.3 Hz), 7.17 (1H, s), 7.24-7.35 (1H, m), 7.51 (2H,d, J=8.7 Hz), 7.57 (2H, d, J=8.7 Hz), 7.60 (1H, s).

IR (KBr): 2959, 1705, 1659, 1590, 1531, 1472 cm⁻¹.

Example 54 Production ofN-(4-(1-(2,6-difluorobenzyl)-3-(2-methoxyethyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 40 by using the compoundobtained in Reference Example 7 (455 mg), diethyl cyanophosphate (228μl), 2-methoxyethylamine (120 mg) and N-ethyldiisopropylamine (310 μl)gave a crude amide (266 mg). Furthermore, the similar reaction by usingmethanol (19.6 ml) and a solution of 28% sodium methoxide in methanol(152 mg) gave the title compound (140 mg).

Elemental analysis for C₂₉H₃₃N₅O₆SF₂

Calcd.: C, 56.39; H, 5.39; N, 11.34.

Found: C, 56.40; H, 5.35; N, 11.15.

¹H-NMR (CDCl₃) δ: 2.14 (3H, s), 2.65 (2H, t, J=5.9 Hz), 3.30 (3H, s),3.36 (3H, s), 3.45 (2H, t, J=5.9 Hz), 3.66 (2H, t, J=5.9 Hz), 3.81 (3H,s), 3.84 (2H, s), 4.30 (2H, t, J=5.9 Hz), 5.33 (2H, s), 6.90 (2H, t,J=8.3 Hz), 7.15 (1H, s), 7.24-7.34 (1H, m), 7.51 (2H, d, J=9.0 Hz), 7.56(2H, d, J=9.0 Hz), 7.60 (1H, m).

IR (KBr): 2936, 1705, 1663, 1590, 1532, 1472 cm⁻¹.

Example 55 Production ofN-(4-(1-(2,6-difluorobenzyl)-3-(2-ethoxyethyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 40 by using the compoundobtained in Reference Example 7 (455 mg), diethyl cyanophosphate (228μl), 2-ethoxyethylamine (143 mg) and N-ethyldiisopropylamine (310 μl)gave a crude amide (259 mg). Furthermore, the similar reaction by usingmethanol (18.7 ml) and a solution of 28% sodium methoxide in methanol(144 mg) gave the title compound (193 mg).

Elemental analysis for C₃₀H₃₅N₅O₆SF₂

Calcd.: C, 57.04; H, 5.58; N, 11.09.

Found: C, 57.01; H, 5.66; N, 10.93.

¹H-NMR (CDCl₃) δ: 1.15 (3H, t, J=6.9 Hz), 2.14 (3H, s), 2.66 (2H, t,J=6.0 Hz), 3.30 (3H, s), 3.45 (2H, t, J=6.0 Hz), 3.54 (2H, q, J=6.9 Hz),3.69 (2H, t, J=6.0 Hz), 3.81 (3H, s), 3.84 (2H, s), 4.29 (2H, t, J=6.0Hz), 5.32 (2H, s), 6.89 (2H, t, J=8.1 Hz), 7.17 (1H, s), 7.23-7.34 (1H,m), 7.52 (2H, d, J=8.7 Hz), 7.57 (2H, d, J=8.7 Hz), 7.60 (1H, m).

IR (KBr): 2975, 1705, 1663, 1590, 1532, 1472 cm⁻¹.

Example 56 Production ofN-(4-(1-(2,6-difluorobenzyl)-3-isopropyl-5-(((2-methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 40 by using the compoundobtained in Reference Example 7 (455 mg), diethyl cyanophosphate (228μl), isopropylamine (95 mg) and N-ethyldiisopropylamine (310 μl) gave acrude amide (306 mg). Furthermore, the stirring with methanol (23.2 ml)and a solution of 28% sodium methoxide in methanol (179 mg) at 60° C.for 17 hours and the similar treatment gave the title compound (192 mg).

Elemental analysis for C₂₉H₃₃N₅O₅SF₂

Calcd.: C, 57.89; H, 5.53; N, 11.64.

Found: C, 57.98; H, 5.49; N, 11.72.

¹H-NMR (CDCl₃) δ: 1.52 (6H, d, J=6.9 Hz), 2.13 (3H, s), 2.66 (2H, t,J=5.9 Hz), 3.31 (3H, s), 3.46 (2H, t, J=5.9 Hz), 3.82 (3H, s), 3.84 (2H,s), 5.31 (2H, s), 5.34 (1H, m), 6.90 (2H, t, J=8.1 Hz), 7.16 (1H, s),7.24-7.35 (1H, m), 7.52 (2H, d, J=8.4 Hz), 7.55 (2H, d, J=8.4 Hz), 7.60(1H, m).

IR (KBr): 2973, 1703, 1659, 1590, 1534, 1472 cm⁻¹.

Example 57 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 40 by using the compoundobtained in Reference Example 7 (455 mg), diethyl cyanophosphate (285μl), 3-amino-6-chloropyridine (243 mg) and N-ethyldiisopropylamine (388μl) gave a crude amide (207 mg). Furthermore, the similar reaction byusing methanol (14.2 ml) and a solution of 28% sodium methoxide inmethanol (109 mg) gave the title compound (132 mg).

¹H-NMR (CDCl₃) δ: 2.13 (3H, s), 2.62 (2H, t, J=5.7 Hz), 3.26 (3H, s),3.41 (2H, t, J=5.7 Hz), 3.74 (2H, brs), 3.82 (3H, s), 4.18 (3H, s), 5.32(2H, brs), 6.92 (2H, t, J=8.3 Hz), 7.12 (1H, d, J=9.3 Hz), 7.24 (1H, s),7.29-7.35 (1H, m), 7.41 (2H, d, J=9.3 Hz), 7.54 (2H, d, J=9.0 Hz), 7.59(2H, d, J=8.7 Hz), 7.66 (1H, s).

IR (KBr): 2936, 1717, 1674, 1591, 1530, 1460 cm⁻¹.

Example 58 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-3-(3-pyridazinyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 40 by using the compoundobtained in Reference Example 7 (364 mg), diethyl cyanophosphate (182μl), 3-aminopyridazine hydrochloride (158 mg) andN-ethyldiisopropylamine (414 μl) gave a crude amide (55 mg).Furthermore, the similar reaction by using methanol (4 ml) and asolution of 28% sodium methoxide in methanol (30 mg) gave the titlecompound (16 mg).

¹H-NMR (CDCl₃) δ: 2.12 (3H, s), 2.61 (2H, t, J=5.7 Hz), 3.26 (3H, s),3.39 (2H, t, J=5.7 Hz), 3.78 (2H, brs), 3.82 (3H, s), 5.34 (2H, brs),6.93 (2H, t, J=8.1 Hz), 7.26 (1H, s), 7.29-7.37 (1H, m), 7.53-7.61 (5H,m), 7.67 (1H, s), 7.69 (1H, dd, J=4.8 Hz, 8.4 Hz), 9.28 (1H, dd, J=1.8Hz, 4.8 Hz).

IR (KBr): 2936, 1717, 1674, 1590, 1530, 1470 cm⁻¹.

Example 59 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-3-methoxy-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 40 by using the compoundobtained in Reference Example 7 (607 mg), diethyl cyanophosphate (304μl), o-methylhydroxylamine hydrochloride (334 mg) andN-ethyldiisopropylamine (1.04 ml) gave a crude product, which waspurified by aminopropyl silica gel column chromatography (Fuji SilysiaChemical) to give the title compound (283 mg).

¹H-NMR (CDCl₃) δ: 2.14 (3H, s), 2.68 (2H, t, J=6.0 Hz), 3.31 (3H, s),3.47 (2H, t, J=6.0 Hz), 3.82 (3H, s), 3.83 (2H, s), 4.06 (3H, s), 5.35(2H, s), 6.92 (2H, t, J=8.3 Hz), 7.20 (1H, s), 7.29-7.35 (1H, m), 7.55(4H, s), 7.63 (1H, s).

IR (KBr): 1725, 1684, 1590, 1530, 1472 cm⁻¹.

Example 60 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 40 by using the compoundobtained in Reference Example 7 (607 mg), diethyl cyanophosphate (304μl), methylamine hydrochloride (270 mg) and N-ethyldiisopropylamine(1.04 ml) gave a crude amide (133 mg). Furthermore, the stirring withmethanol (9.1 ml) and a solution of 28% sodium methoxide in methanol (70mg) at 60° C. for 17 hours and the similar treatment gave the titlecompound (83 mg).

¹H-NMR (CDCl₃) δ: 2.13 (3H, s), 2.66 (2H, t, J=5.9 Hz), 3.31 (3H, s),3.45 (3H, s), 3.48 (2H, t, J=5.9 Hz), 3.82 (3H, s), 3.84 (2H, s), 5.33(2H, s), 6.91 (2H, t, J=8.3 Hz), 7.17 (1H, s), 7.25-7.35 (1H, m), 7.55(4H, s), 7.62 (1H, s).

IR (KBr): 1705, 1661, 1590, 1532, 1472 cm⁻¹.

Reference Example 18 production ofN-(4-(5-chloromethyl-1-(2,6-difluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

Into a solution ofN-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea(7.7 g, 11.53 mmol) in THF (200 ml) which was cooled with a dryice-acetone bath was added α-choloroethyl chloroformate (1.7 ml, 11.64mmol). The temperature of the mixture was elevated up to roomtemperature, and the mixture was stirred for 2.5 hours. The reactionmixture was diluted with saturated aqueous solution of sodium bicabonateand extracted with chloroform. The organic layer was washed withsaturated aqueous solution of sodium chloride, dried over magnesiumsulfate and concentrated under reduced pressure.

The residue was purified with silica gel chromatography (eluent; ethylacetate/chloroform; from 1/4 to 1/3) and recrystallized fromchloroform/diethylether, whereby the title compound (5.66 g, 84%) wasobtained as white crystals.

¹H NMR (CDCl₃) δ 3.83 (3H, s), 4.84 (2H, s), 5.27 (2H, s), 5.37 (2H, s),6.92 (2H, t, J=7.8 Hz), 7.23-7.35 (4H, m), 7.41-7.66 (8H, m).

Reference Example 19 Production ofN-(4-(5-chloromethyl-1-(2,6-difluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxo-3-(4-methoxyphenyl)thieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 5 by using4-(N-benzyl-N-methylaminomethyl)-2-(N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino)-5-(4-(3-methoxyureido)phenyl)thiophene-3-carboxylicacid (5.0 g, 7.83 mmol) and p-anisidine (1.93 g, 15.65 mmol) gaveN-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-3-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea(3.39 g, 62%) as white solids. The similar reaction as described inReference Example 18 by using the compound (80 mg, 0.11 mmol) gave thetitle compound (50 mg, 74%) as white crystals.

¹H NMR (CDCl₃) δ 3.81 (3H, s), 3.83 (3H, s), 4.83 (2H, s), 5.35 (2H, s),6.92 (2H, t, J=8.1 Hz), 7.00 (2H, d, J=10.2 Hz), 7.18-7.35 (3H, m),7.48-7.65 (5H, m).

Reference Example 20 Production ofN-(4-(5-chloromethyl-1-(2,6-difluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxo-3-(4-hydroxycyclohexyl)thieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 5 by using4-(N-benzyl-N-methylaminomethyl)-2-(N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino)-5-(4-(3-methoxyureido)phenyl)thiophene-3-carboxylicacid (10.0 g, 15.65 mmol) and 4-aminocyclohexanol (3.61 g, 31.30 mmol)gaveN-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-3-(4-hydroxycyclohexyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea(5.20 g, 48%) as white crystals. The similar reaction as described inReference Example 18 by using the compound (500 mg, 0.72 mmol) gave thetitle compound (180 mg, 41%) as white crystals.

¹H NMR (CDCl₃) δ 1.41-1.55 (2H, m), 1.71 (2H, d, J=11.7 Hz), 2.07 (2H,d, J=12.4 Hz), 2.63 (2H, q, J=11.1 Hz), 3.70-3.82 (4H, m), 4.84 (2H, s),4.90-5.06 (1H, m), 5.29 (2H, s), 6.91 (2H, t, J=8.1 Hz), 7.13 (1H, s),7.25-7.33 (1H, m), 7.47 (2H, d, J=8.4 Hz), 7.58 (2H, d, J=9.0 Hz), 7.63(1H, s).

Reference Example 21 Production ofN-(4-(5-chloromethyl-1-(2,6-difluorobenzyl)-3-(5-fluoropyridin-2-yl)-1,2,3,4-tetrahydro-2,4-dioxothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 5 by using4-(N-benzyl-N-methylaminomethyl)-2-(N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino)-5-(4-(3-methoxyureido)phenyl)thiophene-3-carboxylicacid (10.0 g, 15.65 mmol) and 2-amino-5-fluoropyridine (3.51 g, 31.30mmol) gaveN-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-3-(5-fluoropyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea(3.39 g, 32%) as white solids. The similar reaction as described inReference Example 18 by using the compound (1.0 g, 1.46 mmol) gave thetitle compound (560 mg, 64%) as white solids.

¹H NMR (CDCl₃) δ 3.83 (1H, s), 4.79 (2H, br), 5.34 (2H, br), 6.93 (2H,t, J=8.0 Hz), 7.14 (1H, s), 7.29-7.40 (2H, m), 7.50-7.65 (5H, m), 8.51(1H, d, J=3.0 Hz).

Reference Example 22 Production ofN-(4-(5-chloromethyl-1-(2,6-difluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxo-3-(pyridin-2-yl)thieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Reference Example 18 by usingcompound (500 mg, 0.75 mmol) obtained in Example 1 gave the titlecompound (270 mg, 62%) as white solids.

¹H NMR (DMDO-d₆) δ 3.63 (3H, s), 4.85 (2H, s), 5.10-5.24 (2H, br), 7.13(2H, t, J=8.3 Hz), 7.41-7.54 (4H, m), 7.78 (2H, d, J=8.4 Hz), 8.01 (1H,t, J=8.0 Hz), 8.30 (1H, s), 8.59-8.61 (1H, m), 9.14 (1H, s), 9.66 (1H,s)

Reference Example 23 Production ofN-(4-(1-(2,6-difluorobenzyl)-3-(4-hydroxycyclohexyl)-5-(methylamino)methyl-1,2,3,4-tetrahydro-2,4-dioxo-thieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Reference Example 14 by usingN-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-3-(4-hydroxycyclohexyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea(5.20 g, 48%) obtained in Reference Example 20 gave the title compound(5.20 g, 48%) as white crystals.

¹H NMR (DMDO-d₆) δ 3.63 (3H, s), 4.85 (2H, s), 5.10-5.24 (2H, br), 7.13(2H, t, J=8.3 Hz), 7.41-7.54 (4H, m), 7.78 (2H, d, J=8.4 Hz), 8.01 (1H,t, J=8.0 Hz), 8.30 (1H, s), 8.59-8.61 (1H, m), 9.14 (1H, s), 9.66 (1H,s)

Reference Example 24 Production ofN-(2-methoxy-1-methylethyl)-N-methylamine

A mixture of a solution of methoxyacetone (2.92 g, 33.14 mmol) andmethylamine in 2.0 M THF (100 ml, 200.0 mmol) and a solution of aceticacid (0.5 ml) in THF (100 ml) was stirred under ice cooling for 30minutes. To the mixture was added triacetoxy sodium borohydride (14.05g, 66.28 mmol), and the mixture was stirred at room temperature for 4days. To the reaction mixture were added saturated aqueous solution ofsodium bicarbonate (100 ml), ethyl acetate ethyl acetate (100 ml) andbenzyloxycarbonylchloride (8.48 g, 49.71 mmol), successively, and themixture was stirred at room temperature for 5 hours. The reactionmixture was distributed between saturated aqueous solution of sodiumbicarbonate and ethyl acetate. The ethyl acetate layer was washed withsaturated brine and dried over magnesium sulfate, and the solvent wasdistilled off. The residue was purified by silica gel chromatography(eluent: ethyl acetate/hexane; from 6/1 to 4/1) to obtain colorlessliquid (4.24 g, 54%). A mixed solution of the colorless liquid (0.94 g,3.96 mmol) and 10% palladium-carbon (94 mg) in ethanol (10 ml) wasstirred at room temperature under hydrogen atmosphere for 2 hours, andsubjected to filtration. The filtrate was concentrated under reducedpressure to give the title compound (220 mg, 54%) as pale yellow liquid.

¹H NMR (CDCl₃) δ 1.15 (3H, d, J=6.6 Hz), 2.50 (3H, s), 2.90-2.99 (1H,m), 3.29-3.44 (5H, m).

Reference Example 25 Production ofN-(4-(5-methylaminomethyl-1-(2,6-difluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxo-3-(4-methoxyphenyl)thieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyureahydrochloride

A mixed solution ofN-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-3-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea(2.0 g, 2.87 mmol) synthesized in Reference Example 19,10%-palladium-carbon (200 mg), 1N hydrochloric acid (3 ml) in ethanol(40 ml) was stirred under hydrogen atmosphere at room temperature for 72hours. The reaction mixture was subjected to filtration and the filtratewas concentrated to dryness to give the title compound (1.77 g, 96%) aswhite powders.

¹H NMR (CDCl₃) δ 2.73 (3H, s), 3.80 (3H, s), 3.85 (3H, s), 4.00-4.18(2H, br), 5.35 (2H, s), 5.37 (2H, s), 6.90-7.08 (4H, m), 7.20-7.38 (5H,m), 7.61 (4H, s), 7.77 (1H, s), 7.95 (1H, s).

Reference Example 26 Production ofN-(4-(5-(((1R)-1-phenylethyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

A solution of the compound (100 mg, 0.17 mmol) obtained in ReferenceExample 18, (R)-(+)-N-α-dimethylbenzylamine (28 mg, 0.21 mmol) andN-ethyldiisopropylamine (29 mg, 0.22 mmol) in DMF (200 ml) was stirredat room temperature for 24 hours. The reaction mixture was diluted withsaturated aqueous solution of sodium bicabonate and extracted with ethylacetate. The organic layer was washed with saturated aqueous solution ofsodium chloride, dried over magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel chromatography(eluent: from ethyl acetate/chloroform(2/3) tochloroform/methanol(20/1)) and recrystallized fromchloroform/diethylether to give the title compound (58 mg, 50%) as whitecrystals.

¹H NMR (CDCl₃) δ 1.25 (3H, d, J=6.6 Hz), 1.89 (3H, s), 3.82 (3H, s),3.82-3.87 (1H, m), 3.91 (2H, d, J=4.5 Hz), 5.35 (2H, s), 6.91 (2H, t,J=8.3 Hz), 7.14-7.30 (9H, m), 7.43-7.61 (8H, m).

mp 192-193° C.

Reference Example 27 Production ofN-(4-(5-((methyl((1S)-1-phenylethyl)amino)methyl)-1-(2,6-difluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Reference Example 26 by usingcompound (100 mg, 0.17 mmol) obtained in Reference Example 18 and(S)-(−)-N-α-dimethylbenzylamine (28 mg, 0.21 mmol) gave the titlecompound (61 mg, 53%) as white crystals.

¹H NMR (CDCl₃) δ 1.25 (3H, d, J=6.6 Hz), 1.89 (3H, s), 3.82 (3H, s),3.82-3.90 (1H, m), 3.91 (2H, d, J=4.5 Hz), 5.35 (2H, s), 6.91 (2H, t,J=8.0 Hz), 7.19-7.30 (9H, m), 7.43-7.61 (8H, m).

mp 191-192° C.

Reference Example 28 Production ofN-(4-(5-(((1R)-1-phenylethylamino)methyl)-1-(2,6-difluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Reference Example 26 by usingcompound (100 mg, 0.17 mmol) obtained in Reference Example 18 and(R)-(+)-1-phenylethylamine (25 mg, 0.21 mmol) gave the title compound(56 mg, 49%) as white crystals.

¹H NMR (CDCl₃) δ 1.32 (3H, d, J=6.6 Hz), 3.59 (1H, d, J=12.0 Hz),3.65-3.82 (5H, m), 5.25-5.46 (2H, AB), 6.90 (2H, t, J=8.1 Hz), 7.11-7.59(13H, m).

Elemental analysis C₃₆H₃₁F₂N₅O₄S.0.2H₂O

Calcd.: C, 64.41; H, 4.71; N, 10.43.

Found: C, 64.29; H, 4.64; N, 10.46.

mp 180-182° C.

Reference Example 29 Production ofN-(4-(5-(((1S)-1-phenylethylamino)methyl)-1-(2,6-difluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Reference Example 26 by using thecompound (100 mg, 0.17 mmol) obtained in Reference Example 18 and(S)-(−)-1-phenylethylamine (25 mg, 0.21 mmol) gave the title compound(56 mg, 49%) as white crystals.

¹H NMR (CDCl₃) δ 1.31 (3H, d, J=6.6 Hz), 3.58 (1H, d, J=12.3 Hz),3.72-3.82 (5H, m), 5.24-5.46 (2H, AB), 6.90 (2H, t, J=8.1 Hz), 7.12 (1H,s), 7.16-7.37 (8H, m), 7.43-7.56 (4H, m).

Elemental analysis C₃₆H₃₁F₂N₅O₄S

Calcd.: C, 64.76; H, 4.68; N, 10.49.

Found: C, 64.46; H, 4.57; N, 10.60.

mp 182-185° C.

Reference Example 30 Production ofN-(4-(5-((methyl(1-phenylpropyl)amino)methyl)-1-(2,6-difluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

Under ice cooling, to a solution of 1-phenyl-1-propanol (1.0 g, 7.34mmol) and N-ethyldiisopropylamine (1.42 g, 11.01 mmol) indichloromethane (10 ml) was added methanesulfonyl chloride (690 μl, 8.81mmol), and the mixture was stirred at room temperature for 5 hours. Thereaction mixture was diluted with saturated aqueous solution of sodiumbicarbonate and extracted with ethyl acetate. The extract was washedwith saturated brine, dried over magnesium sulfate, and solvent wasdistilled off under reduced pressure. The residue was purified by silicagel chromatography (eluent:ethyl acetate/hexane:5/1) to give1-chloro-1-phenylpropane (610 mg, 54%) as pale yellow liquid.

The similar reaction as described in Reference Example 26 by using thecompound (100 mg, 0.17 mmol) obtained in Reference Example 15 and the1-chloro-1-phenylpropane (32 mg, 0.21 mmol) obtained above gave thetitle compound (45 mg, 38%) as white crystals.

¹H NMR (CDCl₃) δ 0.67 (3H, t, J=7.2 Hz), 1.63-1.91 (5H, m), 3.52-3.57(1H, m), 3.73-3.93 (5H, m), 3.91 (2H, d, J=4.5 Hz), 5.35 (2H, s), 6.91(2H, t, J=8.1 Hz), 7.08-7.34 (8H, m), 7.41-7.55 (8H, m), 7.64 (1H, s).

mp 171-172° C.

Reference Example 31 Production ofmethyl(((1-(2,6-difluorobenzyl)-6-(4-(((methoxyamino)carbonyl)amino)phenyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)methyl)(methyl)amino)(phenyl)acetic acid

The similar reaction as described in Example 20 by using the compound(160 mg, 0.17 mmol) obtained in Reference Example 15 andα-bromophenylmethyl acetate (71 mg, 0.31 mmol) gave the title compound(73 mg, 39%) as white crystals.

¹H NMR (CDCl₃) δ 2.08 (3H, s), 3.54 (32H, s), 3.79 (3H, s), 3.89-4.20(2H, AB), 4.67 (1H, s), 5.35 (2H, brs), 6.92 (2H, t, J=8.2 Hz),7.22-7.37 (6H, m), 7.44-7.56 (7H, m) 7.71 (2H, d, J=8.0 Hz).

Elemental analysis C₃₈H₃₃F₂N₅O₆S

Calcd.: C, 62.89; H, 4.58; N, 9.65.

Found: C, 62.70; H, 4.61; N, 9.78.

mp 147-149° C.

Reference Example 32 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-((2-methoxy-1-phenylethyl(methyl)amino)methyl)-1,2,3,4-tetrahydro-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

A solution of methylphenethylether (1.0 g, 7.34 mmol), NBS (1.96 g,11.01 mmol) and AIBN (240 mg, 1.47 mmol) in carbon tetrachloride (30 ml)was heated under reflux for 2 hours. After cooling, the reaction mixturewas diluted with saturated aqueous solution of sodium bicarbonate andextracted with chloroform. The extract was washed with saturated brine,dried over magnesium sulfate and concentrated under reduced pressure togive a crude 2-methoxy-1-phenylbromoethane (1.33 g, 84%) as brownliquid.

The similar reaction as described in Example 14 by using the compound(200 mg, 0.34 mmol) obtained in Reference Example 15 and the crudebromide (60 mg) obtained above gave the title compound (42 mg, 18%) aswhite crystals.

¹H NMR (CDCl₃) δ 1.97 (3H, s), 3.24 (3H, s), 3.55-3.61 (1H, m), 3.80(3H, s), 3.86-3.96 (3H, m), 4.67 (1H, s), 5.36 (2H, s), 6.91 (2H, t,J=8.1 Hz), 7.14-7.31 (8H, m), 7.33-7.56 (8H, m), 7.63 (1H, s).

Elemental analysis C₃₈H₃₅F₂N₅O₅S.0.2H₂O

Calcd.: C, 63.80; H, 4.99; N, 9.79.

Found: C, 63.64; H, 4.95; N, 9.89.

mp 169-172° C.

Reference Example 33 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-((methyl(1-pyridin-2-ylethyl)amino)methyl)-1,2,3,4-tetrahydro-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

A solution of 2-ethylpyridine (10.0 g, 93.34 mmol), N-bromosuccinimide(17.44 g, 98.00 mmol) and azobisisobutyronitrile (1.53 g, 9.33 mmol) incarbon tetrachloride (300 ml) was stirred at 90° C. for 1 hour. Aftercooling, the reaction mixture was subjected to filtration. The filtratewas washed with saturated aqueous solution of sodium bicabonate andsaturated aqueous solution of sodium chloride, dried over magnesiumsulfate and concentrated. The residue was purified by silica gelchromatography to give a bromide (15.68 g, 90%) as pale yellow liquid.

The similar reaction as described in Example 14 by using the compound(160 mg, 0.26 mmol) obtained in Reference Example 15 and the abovebromide (62 mg, 0.33 mmol) obtained above gave the title compound (133mg, 75%) as white crystals.

¹H NMR (CDCl₃) δ 1.30 (3H, d, J=6.9 Hz), 1.92 (3H, s), 3.80 (3H, s),4.00 (2H, s), 4.04 (1H, q, J=6.6 Hz), 5.35 (2H, s), 6.91 (2H, t, J=8.0Hz), 7.02-7.06 (1H, m), 7.24-7.30 (4H, m), 7.40-7.54 (8H, m), 7.65 (1H,s), 8.44 (1H, d, J=5.7 Hz).

mp 146-148° C.

The title compound (40 mg) was optically resolved by a preparative HPLCby using CHIRALPAK AD (60 mmI.D.×500 mL), in which mobile phase ishexane/2-propanol(=3/2), to obtain 19 mg of an optical isomer having anretention time of 25 minutes (99.9% ee) and 19 mg of another isomerhaving retention time of 29 minutes (99.0% ee) in an analysis usingCHIRALPAK AD (4.6 mmI.D.×250 mL), both of which are white powders.

Reference Example 34 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-(((2-methoxy-1-methylethyl)methylamino)methyl)-1,2,3,4-tetrahydro-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Reference Example 26 by using thecompound (100 mg, 0.17 mmol) obtained in Reference Example 18 and thecompound (21 mg, 0.21 mmol) obtained in Reference Example 24 gave thetitle compound (24 mg, 21%) as white crystals.

¹H NMR (CDCl₃) δ 0.90 (3H, d, J=6.3 Hz), 2.04 (3H, s), 3.06-3.16 (2H,m), 3.26 (3H, s), 3.40-3.46 (1H, m), 3.51-3.98 (4H, m), 5.35 (2H, s),6.90 (2H, t, J=8.4 Hz), 7.09 (1H, s), 7.25-7.32 (5H, m), 7.39-7.60 (6H,m).

Elemental analysis C₃₃H₃₃F₂N₅O₅S.0.3H₂O

Calcd.: C, 60.50; H, 5.17; N, 10.69.

Found: C, 60.28; H, 5.21; N, 10.53.

mp 154-155° C.

The title compound (48 mg) was optically resolved by preparative HPLC byusing CHIRALPAK AD (50 mmI.D.×500 mL), in which mobile phase ishexane/2-propanol (65/35), to obtain 22 mg of an optical isomer havingan retention time of 49 minutes (99.0% ee) and 21 mg of another isomerhaving retention time of 54 minutes (99.0% ee) in an analysis usingCHIRALPAK OD (4.6 mmI.D.×250 mL), both of which are white powders.

Reference Example 35 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-((methyl(1-pyridin-2-ylethyl)amino)methyl)-1,2,3,4-tetrahydro-2,4-dioxo-3-(pyridin-2-yl)thieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Reference Example 33 by using thecompound (100 mg, 0.17 mmol) obtained in Reference Example 14 gave thetitle compound (31 mg, 27%) as white crystals.

¹H NMR (CDCl₃) δ 1.30 (3H, d, J=6.9 Hz), 1.92 (3H, s), 3.80 (3H, s),3.98-4.10 (3H, m), 5.33 (2H, brs), 6.90 (2H, t, J=8.1 Hz), 7.01-7.06(1H, m), 7.23-7.42 (5H, m), 7.49-7.56 (4H, m) 7.65 (1H, s), 7.90 (1H, t,J=7.8 Hz), 8.44 (1H, d, J=3.9 Hz), 8.68 (1H, d, J=5.7 Hz).

mp 143-144° C.

The title compound (20 mg) was optically resolved by a preparative HPLCby using CHIRALPAK AD (50 mmI.D.×500 mL), in which mobile phase ishexane/2-propanol (1/1), to obtain 10 mg of an optical isomer having anretention time of 23 minutes (99.9% ee) and 11 mg of another isomerhaving retention time of 28 minutes (99.2% ee) in an analysis usingCHIRALPAK AD (4.6 mmI.D.×250 mL), each of which is colorless oilysubstance.

Reference Example 36 Production ofN-(4-(1-(2,6-difluorobenzyl)-3-(4-hydroxycyclohexyl)-5-((methyl(1-pyridin-2-ylethyl)amino)methyl)-1,2,3,4-tetrahydro-2,4-dioxothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Reference Example 33 by using thecompound (100 mg, 0.17 mmol) obtained in Reference Example 23 gave thetitle compound (17 mg, 14%) as white crystals.

¹H NMR (CDCl₃) δ 1.35 (3H, d, J=6.9 Hz), 1.43-1.54 (2H, m), 1.91 (3H,s), 2.09 (2H, d, J=12.3 Hz), 2.65 (2H, q, J=12.8 Hz), 3.73-3.81 (4H, m),3.98-4.13 (3H, m), 4.60 (1H, t, J=12.0 Hz), 5.28 (2H, brs), 6.88 (2H, t,J=8.1 Hz), 6.89-7.08 (1H, m), 7.22-7.31 (3H, m), 7.40-7.54 (4H, m) 7.62(1H, s), 8.45 (1H, d, J=4.89 Hz).

mp 144-145° C.

Reference Example 37 Production ofN-(4-(5-(((1R)-1-phenylethylamino)methyl)-1-(2,6-difluorobenzyl)-3-(4-hydroxycyclohexyl)-1,2,3,4-tetrahydro-2,4-dioxothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Reference Example 26 by using thecompound (180 mg, 0.30 mmol) obtained in Reference Example 20 gave thetitle compound (77 mg, 37%) as white crystals.

¹H NMR (CDCl₃) δ 1.30 (3H, d, J=6.6 Hz), 1.43-1.57 (2H, m), 1.71 (2H, d,J=9.9 Hz), 1.88 (3H, s), 2.04-2.15 (2H, m), 2.62-2.71 (2H, m), 3.70-3.93(7H, m), 4.90-5.10 (1H, m), 5.28 (2H, s), 6.89 (2H, t, J=8.1 Hz),7.11-7.30 (8H, m), 7.51 (3H, s), 7.60 (1H, s).

Elemental analysis C₃₇H₃₉F₂N₅O₅S.1.5H₂O

Calcd.: C, 60.81; H, 5.79; N, 9.58.

Found: C, 60.77; H, 5.72; N, 9.41.

mp 137-138° C.

Reference Example 38 Production ofN-(4-(5-((methyl((1R)-1-phenylethyl)amino)methyl)-1-(2,6-difluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxo-3-pyridin-2-ylthieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Reference Example 26 by using thecompound (270 mg, 0.46 mmol) obtained in Reference Example 22 gave thetitle compound (178 mg, 57%) as white crystals.

¹H NMR (CDCl₃) δ 1.27 (3H, d, J=6.8 Hz), 1.91 (3H, s), 2.04-2.15 (2H,m), 2.62-2.71 (2H, m), 3.75-4.00 (4H, m), 5.30 (2H, brs), 6.91 (2H, t,J=8.1 Hz), 7.13-7.42 (10H, m), 7.54 (2H, d, J=8.6 Hz), 7.61 (2H, d,J=8.5 Hz), 7.91 (1H, t, J=7.7 Hz), 8.70 (1H, d, J=4.8 Hz).

Elemental analysis C₃₆H₃₂F₂N₆O₄S.0.5H₂O

Calcd.: C, 62.51; H, 4.81; N, 12.15.

Found: C, 62.34; H, 4.71; N, 12.12.

mp 168-170° C.

Reference Example 39 Production ofN-(4-(5-((methyl((1R)-1-phenylethyl)amino)methyl)-1-(2,6-difluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxo-3-(5-fluoropyridin-2-yl)thieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Reference Example 26 by using thecompound (280 mg, 0.46 mmol) obtained in Reference Example 21 gave thetitle compound (187 mg, 58%) as white crystals.

¹H NMR (CDCl₃) δ 1.27 (3H, d, J=6.6 Hz), 1.90 (3H, s), 3.78-3.99 (5H,m), 5.33 (2H, brs), 6.91 (2H, t, J=8.1 Hz), 7.12-7.38 (9H, m), 7.51-7.63(5H, m), 8.52 (1H, d, J=3.0 Hz).

Elemental analysis C₃₆H₃₁F₃N₆O₄S.0.2H₂O

Calcd.: C, 61.39; H, 4.49; N, 11.93.

Found: C, 61.22; H, 4.56; N, 11.96.

mp 128-130° C.

Reference Example 40 Production ofN-(4-(5-(((2-methoxyethyl)methylamino)methyl)-1-(2,6-difluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxo-3-(4-methoxyphenyl)thieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 4 by using the compound(800 mg, 1.24 mmol) obtained in Reference Example 25 and2-bromoethylethylether (207 mg, 1.49 mmol) gave the title compound (407mg, 58%) as white solids.

¹H NMR (CDCl₃) δ 2.13 (3H, s), 2.64 (2H, t, J=5.7 Hz), 3.27 (3H, s),3.41 (2H, t, J=5.6 Hz), 3.82 (3H, s), 3.84 (3H, s), 5.36 (2H, s), 6.92(2H, t, J=8.1 Hz), 7.01 (2H, d, J=8.7 Hz), 7.11 81H, s), 7.19 (2H, d,J=8.7 Hz), 7.26-7.33 (3H, m), 7.53-7.70 (5H, m).

mp 181-184° C.

Reference Example 41 Production of 1-amino-2-methyl-2-propanol

To a suspension of lithium aluminum hydride (2.85 g, 75 mmol) indiethylether (120 ml) was dropwise added a solution of acetonecyanhydrin (4.73 g, 50 mmol) in diethylether (30 ml) under ice cooling.The reaction liquid was stirred at room temperature for 4 hours. To thereaction liquid were dropwise added water (2.85 ml), 1N sodium hydroxide(2.85 ml) and water (8.55 ml), successively. Insoluble matters arefiltered off, and the filtrate was concentrated to give the titlecompound (1.32 g, 30%) as colorless oily substance.

¹H-NMR (CDCl₃) δ: 1.17 (6H, s), 2.60 (2H, s).

Reference Example 42 Production oftert-butyl(3-ethoxy-2,2-dimethylpropoxy)dimethylsilane

To a solution of3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropan-1-ol (Registry No.117932-70-4) (2.18 g, 10 mmol) in THF (30 ml) were added triethylamine(1.67 ml, 12 mmol) and methanesulfonyl chloride (0.85 ml, 11 mmol) underice cooling. The reaction liquid was stirred at room temperature for 30minutes, and to the reaction liquid was added an aqueous solution ofsodium bicarbonate. The mixture was extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure to give the titlecompound (2.98 g, quant.) as colorless oily substance.

¹H-NMR (CDCl₃) δ: 0.04 (6H, s), 0.89 (9H, s), 0.93 (6H, s), 2.98 (3H,s), 3.34 (9H, s), 4.00 (2H, s).

Reference Example 43 Production of2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-1H-isoindol-1,3(2H)-dione

To a solution of compound (2.96 g, 10 mmol) obtained in ReferenceExample 42 in DMF (10 ml) was added potassium phthalimide (1.85 g, 10mmol). The reaction liquid was stirred at 140° C. for 30 hours, andwater was added. The mixture was extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent; ethylacetate/hexane=1/10) to give the title compound (2.79 g, 80%) as paleyellow oily substance.

¹H-NMR (CDCl₃) δ: 0.01 (6H, s), 0.87 (9H, s), 0.93 (6H, s), 3.39 (2H,s), 3.61 (2H, s), 7.65-7.75 (2H, m), 7.8-7.9 (2H, m).

Reference Example 44 Production of 3-amino-2,2-dimethylpropan-1-olhydrochloride

A mixture of compound (1.395 g, 4.0 mmol) obtained in Reference Example43, concentrated hydrochloric acid (10 ml), acetic acid (7 ml) and water(10 ml) was refluxed for 24 hours. The reaction liquid was concentratedand water was added. The precipitated phthalic acid was filtered off andfiltrate was concentrated. The residue was recrystallized from ethylacetate to give the title compound (257.2 mg, 46%) as pale purplecrystals.

¹H-NMR (CDCl₃+CD₃OD) δ: 2.91 (2H, brs), 3.38 (6H, brs), 3.52 (2H, brs).

Reference Example 45 Production of[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopropyl]methanol

To a solution of lithium aluminum hydride (9.34 g, 246 mmol) in THF (150ml) was dropwise added a solution ofdimethylcyclopropane-1,1-dicarboxylate (25.95 g, 164.1 mmol) in THF (150ml) under ice cooling. The solution was stirred at 0° C. for 2 hours,and to the solution were slowly added water (9.5 ml), 15% aqueoussolution of NaOH (9.5 ml) and water (30 ml), successively. Insolublematters were filtered off, and the filtrate was concentrated to givecyclopropane-1,1-dimethylmethanol as colorless oily substance.

To a solution of the above oily substance in 1,2-dimethoxyethane (150ml) was added sodium hydride (60% oil, 6.56 g, 164 mmol), and themixture was stirred at room temperature for 1 hour. To the reactionliquid was dropwise added a solution of tert-butylchlorodimethylsilane(24.7 g, 164 mmol) in 1,2-dimethoxyethane (100 ml), and the mixture wasstirred at room temperature over night. The reaction liquid was pouredinto water and extracted twice with ethyl acetate. The organic layer wasdried over magnesium sulfate and concentrated under reduced pressure.The residue was purified by silicagel column chromatography (eluent;ethyl acetate/hexane=1/15-1/9) to give the title compound (28.19 g, 79%)as colorless oily substance.

¹H-NMR (CDCl₃) δ: 0.07 (6H, s), 0.45-0.54 (4H, m), 0.91 (9H, s), 2.35(1H, brs), 3.56 (2H, s), 3.61 (2H, s).

IR (neat) 3361, 2953, 2856, 1466, 1254, 1088, 1030, 837, 777 cm⁻¹.

Reference Example 46 Production oftert-butyl{[1-(ethoxymethyl)cyclopropyl]methoxy}dimethylsilane

The similar reaction as described in Reference Example 42 by using thecompound (4.33 g, 20 mmol) obtained in Reference Example 45 gave thetitle compound (5.71 g, 97%) as colorless oily substance.

¹H-NMR (CDCl₃) δ: 0.05 (6H, s), 0.55-0.65 (4H, m), 0.89 (9H, s), 3.01(3H, s), 3.52 (2H, s), 4.17 (2H, s).

Reference Example 47 Production of2-{[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopropyl]methyl}-1H-isoindol-1,3(2H)-dione

The similar reaction as described in Reference Example 43 by using thecompound (5.71 g, 19.39 mmol) obtained in Reference Example 46 gave thetitle compound (5.02 g, 75%) as colorless oily substance.

¹H-NMR (CDCl₃) δ: −0.07 (6H, s), 0.45-0.55 (2H, m), 0.65-0.75 (2H, m),0.79 (9H, s), 3.53 (2H, s), 3.74 (2H, s), 7.65-7.75 (2H, m), 7.80-7.90(2H, m).

Reference Example 48 Production of1-[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopropyl]methanamine

To a solution of compound (2.0 g, 5.79 mmol) obtained in ReferenceExample 47 in ethanol (20 ml) was added hydrazine monohydrate (0.42 ml,8.68 mmol) and the mixture was refluxed for 2 hours. Insoluble matterswere filtered off and the filtrate was concentrated. The residue wasdistributed between ethyl acetate and aqueous solution of 1N-sodiumhydroxide, and extracted with ethyl acetate. The organic layer waswashed with brine, dried over magnesium sulfate and concentrated to givethe title compound (1.15 g, 92%) as pale yellow oily substance.

¹H-NMR (CDCl₃) δ: 0.0-0.1 (6H, m), 0.3-0.4 (4H, m), 0.85 (9H, s), 2.61(2H, s), 3.49 (2H, s).

Reference Example 49 Production ofN-(4-(5-chloromethyl-1-(2,6-difluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxo-3-(6-methoxy-3-pyridinyl)thieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Reference Example 18 by using theN-(4-(1-(2,6-difluorobenzyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-3-(6-methoxy-3-pyridinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea(49.3 mg, 0.074 mmol) gave the title compound (44.1 mg, quant.) as whitepowders.

¹H-NMR (CDCl₃) δ: 3.83 (3H, s), 3.97 (3H, s), 4.83 (2H, s), 5.37 (2H,s), 6.87 (1H, d, J=9.0 Hz), 6.94 (2H, t, J=8.4 Hz), 7.13 (1H, s),7.25-7.35 (1H, m), 7.5-7.6 (3H, m), 7.52 (2H, d, J=9.0 Hz), 7.66 (1H,s), 8.1-8.15 (1H, m).

Reference Example 50 Production ofN-(4-(5-chloromethyl-1-(2,6-difluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxo-3-(6-methoxy-3-pyridazinyl)thieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Reference Example 18 by using theN-(4-(1-(2,6-difluorobenzyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea(1.34 g, 2 mmol) gave the title compound (888.5 mg, 71%) as pale yellowpowders.

¹H-NMR (CDCl₃) δ: 3.83 (3H, s), 4.19 (3H, s), 4.7-4.9 (2H, brm),5.3-5.45 (2H, m), 6.93 (2H, t, J=8.0 Hz), 7.14 (1H, d, J=9.0 Hz), 7.16(1H, s), 7.2-7.4 (1H, m), 7.42 (1H, d, J=9.0 Hz), 7.52 (2H, d, J=8.6Hz), 7.62 (2H, d, J=8.6 Hz), 7.69 (1H, s).

Reference Example 51 Production ofN-(4-(1-(2,6-difluorobenzyl)-3-(4-hydroxycyclohexyl)-5-((methylamino)methyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Reference Example 14 by using thecompound (1.75 g, 2.54 mmol) obtained in Example 69 described later gavethe title compound (1.60 g, quant.) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.4-1.9 (3H, m), 2.0-2.2 (2H, m), 2.40 (3H, s),2.5-2.75 (2H, m), 3.77 (2H, s), 3.7-3.85 (1H, m), 3.82 (3H, s), 4.9-5.1(1H, m), 5.30 (2H, s), 6.90 (2H, t, J=8.0 Hz), 7.2-7.35 (2H, m), 7.38(2H, d, J=8.4 Hz), 7.54 (2H, d, J=8.4 Hz), 7.61 (1H, s).

Reference Example 52 Production ofN-(4-(1-(2,6-difluorobenzyl)-3-(2-hydroxypropyl)-5-((methylamino)methyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Reference Example 14 by using thecompound (360 mg, 0.554 mmol) obtained in Example 72 described latergave the title compound (281 mg, 91%) as white powders.

¹H-NMR (CDCl₃) δ: 1.29 (3H, d, J=6.0 Hz), 2.39 (3H, s), 3.80 (2H, s),3.82 (3H, s), 4.1-4.25 (3H, m), 5.34 (2H, s), 6.91 (2H, t, J=8.2 Hz),7.25-7.35 (2H, m), 7.40 (2H, d, J=8.6 Hz), 7.56 (2H, d, J=8.6 Hz), 7.63(1H, s).

Reference Example 53 Production ofN-(4-(1-(2,6-difluorobenzyl)-3-(2-hydroxy-2-methylpropyl)-5-((methylamino)methyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Reference Example 14 by using thecompound (310 mg, 0.467 mmol) obtained in Example 73 described latergave the title compound (241 mg, 90%) as white powders.

¹H-NMR (CDCl₃) δ: 1.28 (6H, s), 2.38 (3H, s), 3.80 (2H, s), 3.82 (3H,s), 3.88 (1H, brs), 4.26 (2H, s), 5.37 (2H, s), 6.91 (2H, t, J=8.1 Hz),7.25-7.35 (2H, m), 7.40 (2H, d, J=8.6 Hz), 7.56 (2H, d, J=8.6 Hz), 7.63(1H, s).

Reference Example 54 Production ofN-(4-(1-(2,6-difluorobenzyl)-3-(6-methoxy-3-pyridazinyl)-5-((methylamino)methyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Reference Example 14 by using thecompound (320 mg, 0.457 mmol) obtained in Example 77 described latergave the title compound (138 mg, 50%) as white powders.

¹H-NMR (CDCl₃) δ: 2.34 (3H, s), 3.77 (2H, s), 3.82 (3H, s), 4.19 (3H,s), 5.35 (2H, s), 6.92 (2H, t, J=8.0 Hz), 7.14 (1H, t, J=9.2 Hz),7.25-7.5 (5H, m), 7.57 (2H, d, J=8.6 Hz), 7.64 (1H, s).

Reference Example 55 Production ofN-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-N′-methoxyurea

The similar reaction as described in Reference Example 26 by using thecompound (130 mg, 0.192 mmol) obtained in Reference Example 19 describedlater and a solution of dimethylamine in THF (0.96 ml, 1.92 mmol) gavethe title compound (43.4 mg, 36%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 2.14 (6H, s), 3.70 (2H, s), 3.82 (3H, s), 3.83 (3H,s), 5.36 (2H, s), 6.92 (2H, t, J=7.8 Hz), 7.01 (1H, d, J=8.7 Hz),7.1-7.35 (4H, m), 7.51 (2H, d, J=8.7 Hz), 7.56 (2H, d, J=8.7 Hz), 7.63(1H, s).

Reference Example 56 Production ofN-{4-[1-(2,6-difluorobenzyl)-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-5-(pyrrolidin-1-ylmethyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-N′-methoxyurea

The similar reaction as described in Reference Example 26 by using thecompound (110 mg, 0.175 mmol) obtained in Reference Example 50 andpyrrolidine (124 mg, 1.75 mmol) gave the title compound (68.1 mg, 60%)as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.5-1.7 (4H, m), 2.35-2.5 (4H, m), 3.82 (3H, s), 3.89(2H, brs), 4.18 (3H, s), 5.34 (2H, brs), 6.92 (2H, t, J=8.8 Hz), 7.12(2H, d, J=9.2 Hz), 7.2-7.35 (2H, m), 7.41 (1H, d, J=9.2 Hz), 7.5-7.6(3H, m), 7.64 (1H, s).

Reference Example 57 Production ofN-{4-[1-(2,6-difluorobenzyl)-3-(6-methoxypyridazin-3-yl)-5-(morpholin-4-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-N′-methoxyurea

The similar reaction as described in Reference Example 26 by using thecompound (110 mg, 0.175 mmol) obtained in Reference Example 50 andmorpholine (152 mg, 1.75 mmol) gave the title compound (78.0 mg, 67%) ascolorless crystals.

¹H-NMR (CDCl₃) δ: 2.35-2.5 (4H, m), 3.5-3.65 (4H, m), 3.76 (2H, s), 3.83(3H, s), 4.19 (3H, s), 5.35 (2H, s), 6.93 (2H, t, J=8.0 Hz), 7.1-7.2(2H, m), 7.2-7.3 (1H, m), 7.40 (1H, d, J=9.0 Hz), 7.5-7.7 (5H, m).

Reference Example 58 Production ofN-(4-(5-((benzyl(2-methoxyethyl)amino)methyl)-1-(2,6-difluorobenzyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Reference Example 26 by using thecompound (120 mg, 0.191 mmol) obtained in Reference Example 50 andN-benzyl-N-(2-methoxyethyl)amine (316 mg, 1.91 mmol) gave the titlecompound (105.1 mg, 74%) as white powders.

¹H-NMR (CDCl₃) δ: 2.67 (2H, t, J=6.2 Hz), 3.18 (3H, s), 3.34 (2H, t,J=6.2 Hz), 3.65 (2H, s), 3.83 (3H, s), 4.03 (2H, s), 4.20 (3H, s), 5.32(2H, brs), 6.92 (2H, t, J=8.2 Hz), 7.1-7.25 (6H, m), 7.25-7.35 (2H, m),7.40 (1H, d, J=9.0 Hz), 7.55 (2H, d, J=8.7 Hz), 7.64 (1H, s), 7.75 (2H,d, J=8.7 Hz).

Elemental analysis C₃₇H₃₅F₂N₇O₆S.1.0H₂O

Calcd.: C, 58.34; H, 4.90; N, 12.87.

Found: C, 58.51; H, 4.58; N, 12.56.

Reference Example 59 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-(((2-methoxyethyl)amino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Reference Example 14 by using thecompound (400 mg, 0.538 mmol) obtained in Reference Example 58 gave thetitle compound (215.9 mg, 61%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 2.72 (2H, t, J=5.6 Hz), 3.28 (3H, s), 3.40 (2H, t,J=5.6 Hz), 3.82 (3H, s), 3.86 (2H, s), 4.19 (3H, s), 5.35 (2H, brs),6.92 (2H, t, J=8.4 Hz), 7.14 (2H, d, J=9.0 Hz), 7.25-7.35 (1H, m), 7.39(2H, d, J=9.0 Hz), 7.43 (2H, d, J=8.8 Hz), 7.56 (2H, d, J=8.8 Hz), 7.64(1H, s).

Elemental analysis C₃₀H₂₉F₂N₇O₆S.0.5H₂O

Calcd.: C, 54.38; H, 4.56; N, 14.80.

Found: C, 54.62; H, 4.39; N, 14.62.

Example 61 Production ofN-(4-(1-(2,6-difluorobenzyl)-3-(2-hydroxypropyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 5 by using the compound(1.82 g, 3 mmol) obtained in Reference Example 7 and 1-amino-2-propanol(0.45 g, 6 mmol) gave the title compound (1.11 g, 60%) as white powders.

¹H-NMR (CDCl₃) δ: 1.27 (3H, d, J=5.6 Hz), 2.12 (3H, s), 2.64 (2H, t,J=5.8 Hz), 2.9-3.05 (1H, m), 3.30 (3H, s), 3.45 (2H, d, J=5.8 Hz), 3.82(5H, s), 4.05-4.25 (1H, m), 4.18 (2H, s), 5.34 (2H, s), 6.91 (2H, t,J=8.2 Hz), 7.2-7.4 (1H, m), 7.5-7.6 (3H, m), 7.63 (1H, s).

Elemental analysis C₂₉H₃₃F₂N₅O₆S.0.7H₂O

Calcd.: C, 55.26; H, 5.50; N, 11.11.

Found: C, 55.42; H, 5.52; N, 10.75.

Example 62 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-3-(2-oxopropyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

To a solution of oxalyl chloride (0.20 g, 1.58 mmol) in dichloromethane(2 ml) was dropwise added a solution of dimethylsulfoxide (163 mg, 2.09mmol) in dichloromethane (2 ml) under cooling at −78° C. After stirringfor 10 minutes, a solution of the compound (308 mg, 0.5 mmol) obtainedin Example 61 in dichloromethane (2 ml) was dropwise added. Afterstirring for further 30 minutes, triethylamine (0.40 ml, 2.88 mmol) wasdropwise added, and the mixture was stirred at 0° C. for 2 hours. To themixture was added an aqueous solution of ammonium chloride at 0° C., andthe mixture was extracted with ethyl acetate. The organic layer waswashed with brine, dried over anhydrous magnesium sulfate, andconcentrated with under reduced pressure. The residue was purified byNH-silica gel (Produced by Fuji Silysia Chemical Ltd.) columnchromatography (eluent; ethyl acetate), and the obtained powders waswashed with diisopropyl ether and hexane to give the title compound(40.7 mg, 13%) as pale yellow powders.

¹H-NMR (CDCl₃) δ: 2.13 (3H, s), 2.27 (3H, s), 2.55-2.65 (2H, m), 3.29(3H, s), 3.4-3.5 (2H, m), 3.82 (5H, s), 4.88 (2H, s), 5.33 (2H, s), 6.91(2H, t, J=8.0 Hz), 7.2-7.35 (1H, m), 7.5-7.65 (4H, m).

Example 63 Production ofN-(4-(1-(2,6-difluorobenzyl)-3-(3,3-dimethyl-2-oxobutyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 5 by using the compound(303 mg, 0.5 mmol) obtained in Reference Example 7 and3,3-dimethyl-2-oxobutylamine hydrochloride (U.S. Pat. No. 6,096,688)(152 mg, 1 mmol) gave the title compound (195.7 mg, 60%) as pale yellowcrystals.

¹H-NMR (CDCl₃) δ: 1.30 (9H, s), 2.12 (3H, s), 2.62 (2H, t, J=5.8 Hz),3.29 (3H, s), 3.44 (2H, d, J=5.8 Hz), 3.80 (2H, s), 3.82 (3H, s), 5.04(2H, s), 5.33 (2H, s), 6.91 (2H, t, J=8.2 Hz), 7.14 (1H, s), 7.2-7.3(1H, m), 7.5-7.6 (4H, m), 7.61 (1H, s).

Elemental analysis C₃₂H₃₇F₂N₅O₆S

Calcd.: C, 58.43; H, 5.67; N, 10.65.

Found: C, 58.15; H, 5.71; N, 10.42.

Example 64 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-3-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 5 by using the compound(303 mg, 0.5 mmol) obtained in Reference Example 7 and2,2,2-trifluoroethylamine (99 mg, 1 mmol) gave the title compound (52.9mg, 16%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 2.12 (3H, s), 2.65 (2H, t, J=6.0 Hz), 3.31 (3H, s),3.45 (2H, d, J=6.0 Hz), 3.82 (5H, s), 4.75-4.85 (2H, m), 5.36 (2H, s),6.92 (2H, t, J=8.2 Hz), 7.13 (1H, s), 7.2-7.35 (1H, m), 7.55-7.6 (4H,m), 7.62 (1H, s).

Elemental analysis C₂₈H₂₈F₅N₅O₅S.1.0H₂O

Calcd.: C, 50.98; H, 4.58; N, 10.62.

Found: C, 51.14; H, 4.44; N, 10.34.

Example 65 Production ofN-(4-(1-(2,6-difluorobenzyl)-3-(2-hydroxy-3,3-dimethylbutyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

To a mixed solution of compound (120 mg, 0.182 mmol) obtained in Example63 in methanol (6 ml) and THF (4 ml) was added sodium borohydride (6.9mg, 0.182 mmol) under ice cooling. The reaction liquid was stirred atroom temperature for 1.5 hours and concentrated under reduced pressure.The residue was distributed between water and ethyl acetate, and theorganic layer was extracted. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by NH-silica gel (Produced by FujiSilysia Chemical Ltd.) column chromatography (eluent; ethyl acetate),and recrystallized from ethyl acetate and diethylether to give the titlecompound (81.1 mg, 68%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.04 (9H, s), 2.12 (3H, s), 2.64 (2H, t, J=6.0 Hz),2.96 (1H, d, J=6.0 Hz), 3.31 (3H, s), 3.46 (2H, d, J=6.0 Hz), 3.5-3.6(1H, m), 3.82 (3H, s), 3.75-3.9 (2H, m), 4.05-4.2 (1H, m), 4.3-4.45 (1H,m), 5.25-5.45 (2H, m), 6.91 (2H, t, J=8.2 Hz), 7.14 (1H, s), 7.2-7.35(1H, m), 7.5-7.6 (4H, m), 7.61 (1H, s).

Elemental analysis C₃₂H₃₉F₂N₅O₆S.0.2H₂O

Calcd.: C, 57.94; H, 5.99; N, 10.56.

Found: C, 57.89; H, 5.91; N, 10.43.

Example 66 Production ofN-(4-(1-(2,6-difluorobenzyl)-3-(2-hydroxy-2-methylpropyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 5 by using the compound(303 mg, 0.5 mmol) obtained in Reference Example 7 and compound (89 mg,1 mmol) obtained in Reference Example 41 gave the title compound (133.9mg, 42%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.28 (6H, s), 2.3 (3H, s), 2.64 (2H, t, J=5.8 Hz),3.30 (3H, s), 3.45 (2H, t, J=5.8 Hz), 3.82 (5H, s), 3.99 (1H, s), 4.25(2H, s), 5.36 (2H, s), 6.91 (2H, t, J=8.2 Hz), 7.12 (1H, s), 7.2-7.4(1H, m), 7.5-7.6 (4H, m), 7.61 (1H, s).

Elemental analysis C₃₀H₃₅F₂N₅O₆S.0.1H₂O

Calcd.: C, 56.88; H, 5.60; N, 11.06.

Found: C, 56.65; H, 5.54; N, 10.85.

Example 67 Production ofN-[4-(1-(2,6-difluorobenzyl)-3-(3-hydroxy-2,2-dimethylpropyl)-5-{[(2-methoxyethyl)(methyl)amino]methyl}-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl]-N′-methoxyurea

The similar reaction as described in Example 5 by using the compound(303 mg, 0.5 mmol) obtained in Reference Example 7 and compound (140 mg,1 mmol) obtained in Reference Example 44 gave the title compound (36.8mg, 11%) as pale yellow crystals.

¹H-NMR (CDCl₃) δ: 0.96 (6H, s), 2.13 (3H, s), 2.64 (2H, t, J=6.2 Hz),3.13 (2H, s), 3.30 (3H, s), 3.45 (2H, t, J=6.2 Hz), 3.82 (5H, s),3.95-4.15 (2H, brm), 5.1-5.5 (2H, br), 6.91 (2H, t, J=8.2 Hz), 7.14 (1H,s), 7.2-7.4 (1H, m), 7.5-7.6 (4H, m), 7.61 (1H, s).

HPLC (220 nm) Purity 90% (Retention time 1.83 minutes)

MS (ESI+, m/e) 646 (M+1)

Example 68 Production ofN-(4-(1-(2,6-difluorobenzyl)-3-((1-(hydroxymethyl)cyclopropyl)methyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 5 by using the compound(606 mg, 1 mmol) obtained in Reference Example 7 and compound (431 mg, 2mmol) obtained in Reference Example 47 gave the thienopyrimidinecyclized form (549.3 mg, 72%). The above cyclized form was dissolved inTHF (10 ml), and a solution of tetrabutylammoniumfluoride in 1M THF (1.7ml, 1.7 mmol) was added. The mixture was stirred at room temperature for20 hours. The reaction liquid was distributed between water and ethylacetate, and the organic layer was extracted. The organic layer waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified byNH-silica gel (Produced by Fuji Silysia Chemical Ltd.) columnchromatography (eluent; ethyl acetate), and recrystallized from ethylacetate and diethylether to give the title compound (196.1 mg, 43%) ascolorless crystals.

¹H-NMR (CDCl₃) δ: 0.46 (2H, t, J=5.4 Hz), 0.85 (2H, t, J=5.4 Hz), 2.11(3H, s), 2.64 (2H, t, J=6.0 Hz), 3.25 (2H, s), 3.31 (3H, s), 3.46 (2H,t, J=6.0 Hz), 3.82 (5H, s), 3.95-4.15 (1H, br), 4.14 (2H, s), 5.37 (2H,s), 6.91 (2H, t, J=8.0 Hz), 7.12 (1H, s), 7.2-7.4 (1H, m), 7.54 (4H, s),7.61 (1H, s).

Elemental analysis C₃₁H₃₅F₂N₅O₆S

Calcd.: C, 57.84; H, 5.48; N, 10.88.

Found: C, 57.63; H, 5.46; N, 10.86.

Example 69 Production ofN-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-3-(4-hydroxycyclohexyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 5 by using4-(N-benzyl-N-methylaminomethyl)-2-[N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino]-5-[4-(3-methoxyureido)phenyl]thiophene-3-carboxylicacid (3.19 g, 5 mmol) and trans-4-aminocyclohexanol (1.44 g, 12.5 mmol)gave the title compound (1.80 g, 52%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.35-1.65 (3H, m), 1.65-1.8 (2H, m), 2.07 (3H, s),2.5-2.8 (2H, m), 3.58 (2H, s), 3.7-3.9 (1H, m), 3.82 (3H, s), 3.91 (2H,s), 4.9-5.1 (1H, m), 5.29 (2H, s), 6.90 (2H, t, J=7.8 Hz), 7.13 (1H, s),7.15-7.35 (6H, m), 7.53 (2H, d, J=8.6 Hz), 7.61 (1H, s), 7.66 (2H, d,J=8.6 Hz).

Elemental analysis C₃₆H₃₇F₂N₅O₆S.0.5H₂O

Calcd.: C, 61.09; H, 5.55; N, 9.89.

Found: C, 61.41; H, 5.65; N, 9.56.

Example 70 Production ofN-[4-(1-(2,6-difluorobenzyl)-3-(4-hydroxycyclohexyl)-5-{[(2-methoxyethyl)(methyl)amino]methyl}-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl]-N′-methoxyurea

The similar reaction as described in Example 4 by using the compound(300 mg, 0.5 mmol) obtained in Reference Example 51 and2-bromoethylmethylether (0.69 g, 5 mmol) gave the title compound (75.1mg, 23%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.2-1.6 (3H, m), 1.6-1.8 (2H, m), 2.0-2.1 (2H, m),2.14 (3H, s), 2.5-2.75 (4H, m), 3.31 (3H, s), 3.45 (2H, t, J=5.8 Hz),3.65-3.85 (3H, m), 3.82 (3H, s), 4.9-5.05 (1H, br), 5.30 (2H, s), 6.90(2H, t, J=8.0 Hz), 7.12 (1H, s), 7.25-7.4 (1H, m), 7.5-7.6 (4H, m), 7.60(1H, s).

Elemental analysis C₃₂H₃₇F₂N₅O₆S.0.5H₂O

Calcd.: C, 57.65; H, 5.74; N, 10.50.

Found: C, 57.54; H, 5.75; N, 10.64.

Example 71 Production ofN-{4-[1-(2,6-difluorobenzyl)-5-{[(2-methoxyethyl)(methyl)amino]methyl}-3-(6-methylpyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-N′-methoxyurea

The similar reaction as described in Example 5 by using the compound(303 mg, 0.5 mmol) obtained in Reference Example 7 and3-amino-6-methylpyridazine (136 mg, 1.25 mmol) gave the title compound(48.3 mg, 15%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 2.13 (3H, s), 2.61 (2H, t, J=5.8 Hz), 2.79 (3H, s),3.26 (3H, s), 3.41 (2H, t, J=5.8 Hz), 3.75-3.85 (2H, m), 3.82 (3H, s),5.25-5.45 (2H, brm), 6.92 (2H, t, J=8.2 Hz), 7.18 (1H, s), 7.2-7.7 (8H,m).

Example 72 Production ofN-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-3-(2-hydroxypropyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 5 by using4-(N-benzyl-N-methylaminomethyl)-2-[N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino]-5-[4-(3-methoxyureido)phenyl]thiophene-3-carboxylicacid (639 mg, 1 mmol) and 1-amino-2-propanol (0.19 g, 2.5 mmol) gave thetitle compound (409.7 mg, 63%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.30 (3H, d, J=6.0 Hz), 2.06 (3H, s), 2.90 (1H, d,J=5.2 Hz), 3.57 (2H, s), 3.82 (3H, s), 3.91 (2H, s), 4.1-4.25 (1H, m),4.20 (2H, s), 5.34 (2H, s), 6.91 (2H, t, J=8.0 Hz), 7.16 (1H, s),7.2-7.4 (6H, m), 7.54 (2H, d, J=8.8 Hz), 7.62 (1H, s), 7.67 (2H, d,J=8.8 Hz).

Elemental analysis C₃₃H₃₃F₂N₅O₅S

Calcd.: C, 61.00; H, 5.12; N, 10.78.

Found: C, 60.82; H, 5.21; N, 10.68.

Example 73 Production ofN-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-3-(2-hydroxy-2-methylpropyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 5 by using the4-(N-benzyl-N-methylaminomethyl)-2-[N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino]-5-[4-(3-methoxyureido)phenyl]thiophene-3-carboxylicacid (639 mg, 1 mmol) and compound (0.22 g, 2.5 mmol) obtained inReference Example 41 gave the title compound (360.9 mg, 54%) ascolorless crystals.

¹H-NMR (CDCl₃) δ: 1.29 (6H, s), 2.06 (3H, s), 3.56 (2H, s), 3.83 (3H,s), 3.91 (2H, s), 3.96 (1H, s), 4.28 (2H, s), 5.36 (2H, s), 6.91 (2H, t,J=8.2 Hz), 7.13 (1H, s), 7.2-7.35 (6H, m), 7.54 (2H, d, J=8.8 Hz), 7.62(1H, s), 7.67 (2H, d, J=8.8 Hz).

Elemental analysis C₃₄H₃₅F₂N₅O₅S

Calcd.: C, 61.53; H, 5.32; N, 10.55.

Found: C, 61.30; H, 5.32; N, 10.32.

Example 74 Production ofN-(4-(1-(2,6-difluorobenzyl)-3-(2-hydroxypropyl)-5-((methyl(2-(2-pyridinyl)ethyl)amino)methyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 2 by using the compound(260 mg, 0.465 mmol) obtained in Reference Example 52 and2-(2-hydroxyethyl)pyridine (400 mg, 1.63 mmol) gave the title compound(195.9 mg, 63%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.28 (3H, d, J=5.8 Hz), 2.21 (3H, s), 2.75-2.95 (4H,m), 3.0-3.1 (1H, m), 3.82 (5H, s), 4.1-4.2 (1H, m), 4.17 (2H, s), 5.34(2H, s), 6.91 (2H, t, J=8.2 Hz), 6.95-7.1 (2H, m), 7.14 (1H, s), 7.2-7.4(1H, m), 7.4-7.55 (5H, m), 7.59 (1H, s), 8.43 (1H, d, J=5.0 Hz).

Elemental analysis C₃₃H₃₄F₂N₆O₅S.0.2H₂O

Calcd.: C, 59.31; H, 5.19; N, 12.57.

Found: C, 59.24; H, 5.29; N, 12.32.

Example 75 Production ofN-(4-(1-(2,6-difluorobenzyl)-3-(2-hydroxy-2-methylpropyl)-5-((methyl(2-(2-pyridinyl)ethyl)amino)methyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 2 by using the compound(220 mg, 0.384 mmol) obtained in Reference Example 53 and2-(2-hydroxyethyl)pyridine (800 mg, 3.25 mmol) gave the title compound(138.2 mg, 53%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.26 (6H, s), 2.21 (3H, s), 2.75-2.95 (4H, m), 3.82(5H, s), 3.99 (1H, s), 4.24 (2H, s), 5.36 (2H, s), 6.91 (2H, t, J=8.2Hz), 7.0-7.1 (2H, m), 7.13 (1H, s), 7.2-7.35 (1H, m), 7.45-7.55 (5H, m),7.59 (1H, s), 8.43 (1H, d, J=4.0 Hz).

Elemental analysis C₃₄H₃₆F₂N₆O₅S.0.1H₂O

Calcd.: C, 59.85; H, 5.38; N, 12.32.

Found: C, 59.81; H, 5.45; N, 12.03.

Example 76 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-3-(2-pyrazinyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 5 by using the compound(303 mg, 0.5 mmol) obtained in Reference Example 7 and aminopyrazine(119 mg, 1.25 mmol) gave the title compound (35.2 mg, 11%) as colorlesscrystals.

¹H-NMR (CDCl₃) δ: 2.13 (3H, s), 2.62 (2H, t, J=6.0 Hz), 3.26 (3H, s),3.41 (2H, t, J=6.0 Hz), 3.79 (2H, s), 3.83 (1H, s), 5.36 (2H, s), 6.94(2H, t, J=8.0 Hz), 7.12 (1H, s), 7.2-7.4 (1H, m), 7.5-7.65 (5H, m),8.65-8.7 (3H, m).

Elemental analysis C₃₀H₂₉F₂N₇O₅S.0.1H₂O

Calcd.: C, 56.35; H, 4.60; N, 15.33.

Found: C, 56.20; H, 4.52; N, 15.16.

Example 77 Production ofN-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 5 by using4-(N-benzyl-N-methylaminomethyl)-2-[N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino]-5-[4-(3-methoxyureido)phenyl]thiophene-3-carboxylicacid (1.28 g, 2 mmol) and 6-chloro-3-aminopyridazine (648 mg, 5 mmol)gave the title compound (0.36 g, 26%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 2.06 (3H, s), 3.55 (2H, s), 3.83 (3H, s), 3.87 (2H,s), 4.19 (3H, s), 5.35 (2H, s), 6.92 (2H, t, J=8.2 Hz), 7.1-7.45 (9H,m), 7.55 (2H, d, J=8.4 Hz), 7.63 (1H, s), 7.72 (2H, d, J=8.4 Hz).

Example 78 Production ofN-(4-(1-(2,6-difluorobenzyl)-3-(6-methoxy-3-pyridazinyl)-5-((methyl(2-(2-pyridinyl)ethyl)amino)methyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 2 by using the compound(135 mg, 0.221 mmol) obtained in Reference Example 54 and2-(2-hydroxyethyl)pyridine (272 mg, 2.21 mmol) gave the title compound(79.6 mg, 50%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 2.20 (3H, s), 2.7-2.9 (4H, m), 3.78 (2H, s), 3.82 (3H,s), 4.19 (3H, s), 5.34 (2H, s), 6.85-7.2 (5H, m), 7.25-7.45 (2H, m),7.45-7.7 (7H, m), 8.42 (1H, d, J=4.0 Hz).

Elemental analysis C₃₅H₃₂F₂N₈O₅S.1.0H₂O

Calcd.: C, 57.37; H, 4.68; N, 15.29.

Found: C, 57.29; H, 4.60; N, 15.15.

Example 79 Production ofN-(4-(5-((methyl(2-pyridin-2-ylethyl)amino)methyl)-1-(2,6-difluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxo-3-(4-methoxyphenyl)thieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 2 by using the compound(800 mg, 1.24 mmol) obtained in Reference Example 25 and2-(2-hydroxyethyl)pyridine (300 mg, 1.49 mmol) gave the title compound(407 mg, 58%) as white solids.

¹H NMR (CDCl₃) δ2.20 (3H, s), 2.86 (4H, m), 3.82-3.84 (8H, m), 5.36 (2H,s), 6.92 (2H, t, J=8.3 Hz), 7.00-7.06 (4H, m), 7.14-7.33 (4H, m),7.46-7.51 (5H, m), 7.61 (1H, s), 8.42 (1H, d, J=5.7 Hz).

Elemental analysis C₃₇H₃₄F₂N₆O₅S.0.7H₂O

Calcd.: C, 61.26; H, 4.92; N, 11.59.

Found: C, 61.06; H, 4.86; N, 11.52.

Example 80 Production ofN-[4-(1-(2,6-difluorobenzyl)-3-(6-hydroxypyridazin-3-yl)-5-{[(2-methoxyethyl)(methyl)amino]methyl}-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl]-N′-methoxyurea

To a solution of the compound (1.34 g, 2 mmol) obtained in Example 57 inTHF (30 ml) was added a solution of 4N HCl in acetic acid (2 ml, 8mmol), and the mixture was stirred at room temperature for 20 hours, at50° C. for 10 hours and further at 60° C. for 3 hours. The reactionliquid was distributed between aqueous solution of sodium bicarbonateand ethyl acetate, and the organic layer was extracted. The aqueouslayer was subjected to salting-out, and extracted with ethyl acetate.The organic layers were collected and combined and the organic layer wasdried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by NH-silica gel (Produced by FujiSilysia Chemical Ltd.) column chromatography (eluent; ethylacetate/methanol=8/1). To the eluate was added diisopropylether to givepowders. The powders were collected by filtration, washed withdiisopropylether to obtain the title compound (539 mg, 41%) as a paleyellow powder.

¹H-NMR (CDCl₃) δ: 2.12 (3H, s), 2.63 (2H, t, J=5.8 Hz), 3.28 (3H, s),3.43 (2H, t, J=5.8 Hz), 3.79 (2H, s), 3.83 (3H, s), 5.35 (2H, s), 6.94(2H, t, J=8.2 Hz), 7.0-7.1 (1H, m), 7.2-7.4 (3H, m), 7.5-7.65 (4H, m),7.63 (1H, s), 10.5-10.6 (1H, brs).

Elemental analysis C₃₀H₂₉F₂N₇O₆S.2.0H₂O

Calcd.: C, 52.24; H, 4.82; N, 14.22.

Found: C, 52.24; H, 4.57; N, 14.06.

Example 81 Production ofN-{4-[1-(2,6-difluorobenzyl)-5-{[(2-hydroxyethyl)(methyl)amino]methyl}-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-N′-methoxyurea

The similar reaction as described in Example 4 by using the compound(305 mg, 0.5 mmol) obtained in Reference Example 54 and 2-bromoethanol(0.62 g, 5 mmol) gave the title compound (145.7 mg, 45%) as colorlesscrystals.

¹H-NMR (CDCl₃) δ: 1.98 (3H, s), 2.45-2.5 (2H, m), 2.9-3.2 (1H, m),3.5-3.55 (2H, m), 3.65-3.85 (2H, brm), 3.82 (3H, s), 4.18 (3H, s), 5.34(2H, s), 6.93 (2H, t, J=8.0 Hz), 7.11 (1H, d, J=9.0 Hz), 7.18 (1H, s),7.25-7.35 (1H, m), 7.35-7.45 (3H, m), 7.57 (2H, d, J=8.7 Hz), 7.66 (1H,s).

Elemental analysis C₃₀H₂₉F₂N₇O₆S.0.6H₂O

Calcd.: C, 54.23; H, 4.58; N, 14.76.

Found: C, 53.98; H, 4.61; N, 14.72.

Example 82 Production ofN-{4-[1-(2,6-difluorobenzyl)-5-{[(2-hydroxyethyl)(methyl)amino]methyl}-3-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-N′-methoxyurea

The similar reaction as described in Example 4 by using the compound(123 mg, 0.191 mmol) obtained in Reference Example 25 and 2-bromoethanol(239 mg, 1.91 mmol) gave the title compound (47.1 mg, 39%) as colorlesscrystals.

¹H-NMR (CDCl₃) δ: 1.99 (3H, s), 2.45-2.55 (2H, m), 3.5-3.6 (2H, m), 3.79(2H, s), 3.82 (3H, s), 3.83 (3H, s), 5.36 (2H, s), 6.92 (2H, t, J=8.0Hz), 6.99 (2H, d, J=8.8 Hz), 7.1-7.3 (4H, m), 7.39 (2H, d, J=8.8 Hz),7.56 (2H, d, J=8.8 Hz), 7.64 (1H, s).

Example 83 Production ofN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

The similar reaction as described in Example 4 by using the compound(100 mg, 0.164 mmol) obtained in Reference Example 54 and methyl iodide(0.010 ml, 0.164 mmol) gave the title compound (17.3 mg, 17%) ascolorless crystals.

¹H-NMR (CDCl₃) δ: 2.15 (6H, s), 3.6-3.8 (2H, m), 3.82 (3H, s), 4.18 (3H,s), 5.35 (2H, s), 6.92 (2H, t, J=8.2 Hz), 7.12 (1H, d, J=8.8 Hz),7.2-7.65 (7H, m), 7.69 (1H, s).

Example 84 Production ofN-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-N′-methoxyurea

The similar reaction as described in Reference Example 26 by using thecompound (41.1 mg, 0.067 mmol) obtained in Reference Example 49 and asolution of dimethylamine in THF (0.67 ml, 1.34 mmol) gave the titlecompound (18.4 mg, 44%) as white powders.

¹H-NMR (CDCl₃) δ: 2.13 (6H, s), 3.68 (2H, s), 3.83 (3H, s), 3.96 (3H,s), 5.36 (2H, s), 6.8-7.0 (3H, m), 7.13 (1H, s), 7.2-7.4 (1H, m),7.45-7.65 (6H, m), 8.10 (1H, d, J=2.6 Hz).

Preparation 1

By a conventional manner, tablet is prepared by using the compoundobtained in Example 40 (100 mg), lactose (165 mg), corn starch (25 mg),polyvinyl alcohol (4 mg) and magnesium stearate (1 mg).

Preparation 2

The compound obtained in Example 40 (5 g) was dissolved in distilledwater for injection to make the total volume to 100 ml. The solution wassubjected to sterile filtration by using membrane filter having adiameter of 0.22 μm (Produced by Sumitomo Electric Industries, Ltd. orSartorius K.K.), 2 ml each of the solution is poured into a sterilizedvial, and is freeze dried in a conventional manner to give freeze-driedinjectable preparation.

Preparation 3

By a conventional manner a tablet is prepared by using compound obtainedin Example 41 (100 mg), lactose (165 mg), corn starch (25 mg), polyvinylalcohol (4 mg) and magnesium stearate (1 mg).

Preparation 4

The compound obtained in Example 41 (5 g) was dissolved in distilledwater for injection to make the total volume to 100 ml. The solution wassubjected to sterile filtration by using membrane filter having adiameter of 0.22 μm (Produced by Sumitomo Electric Industries, Ltd. orSartorius K.K.), 2 ml each of the solution is poured into a sterilizedvial, and is freeze dried in a conventional manner to give freeze-driedinjectable preparation.

Preparation 5  (1) Compound obtained in Example 40 or Example 41 5 g (2) lactose · crystalline cellulose (grain) 330 g  (3) D-mannitol 29 g (4) low substituted hydroxypropylcellulose 20 g  (5) talc 25 g  (6)hydroxypropylcellulose 50 g  (7) aspartame 3 g  (8) dipotassiumglycyrrhizinate 3 g  (9) hydroxypropylmethylcellulose 2910 30 g (10)titanium oxide 3.5 g (11) ferric oxide yellow 0.5 g (12) light silicicacid anhydride 1 g

The above (1), (3), (4), (5), (6), (7) and (8) are suspended ordissolved in purified water, nuclear particles of (2) are coated withthe solution to prepare crude fine grains. The crude fine grains arecoated with (9) to (11) to prepare coated fine grains. They are mixedwith (12) to prepare 1% KM05283 fine grains (500 g). 500 mg each of thefine grains are wrapped, separately.

Experimental Example 1 (1) Preparation of ¹²⁵I-Leuprorelin

To a tube containing 10 μl of a 3×10⁻⁴ M aqueous solution of leuprorelinand 10 μl of 0.01 mg/ml lactoperoxidase was added 10 μl (37 MBq) of asolution of Na¹²⁵I. After stirring, 10 μl of 0.001% H₂O₂ was added, anda reaction was carried out at room temperature for 20 minutes. By adding700 μl of a 0.05% TFA solution, the reaction was stopped, followed bypurification by reversed-phase HPLC. The HPLC conditions used are shownbelow. ¹²⁵I-leuprorelin was eluted at a retention time of 26 to 27minutes.

Column: TSKgel ODS-80™ (TM indicates a registered trademark; the sameapplies below) CTR (4.6 mm×10 cm)

Eluents: Solvent A (0.05% TFA)

-   -   Solvent B (40% CH₃CN-0.05% TFA)    -   0 minute (100% Solvent A)-3 minutes (100% Solvent A)-7 minutes        (60% Solvent A+50% Solvent B)-40 minutes (100% Solvent B)        Eluting temperature: Room temperature

Elution rate: 1 ml/min

(2) Preparation of CHO (Chinese Hamster Ovarian) Cell Membrane FractionContaining Monkey GnRH Receptor

Monkey GnRH receptor-expressing CHO cells (10⁹ cells) were suspended inphosphate-buffered saline supplemented with 5 mM EDTA (PBS-EDTA) andcentrifuged at 100×g for 5 minutes. To the cell pellet, 10 ml of a cellhomogenate buffer (10 mM NaHCO₃, 5 mM EDTA, pH 7.5) was added, followedby homogenization using the Polytron homogenizer. After centrifugationat 400×g for 15 minutes, the supernatant was transferred to anultracentrifugation tube and centrifuged at 100,000×g for 1 hour toyield a membrane fraction precipitate. This precipitate was suspended in2 ml of an assay buffer and centrifuged at 100,000×g for 1 hour. Themembrane fraction recovered as a precipitate was again suspended in 20ml of the assay buffer, dispensed, and stored at −80° C. before use uponthawing.

(3) Preparation of CHO (Chinese Hamster Ovarian) Cell Membrane FractionContaining Human GnRH Receptor

Human GnRH receptor-expressing CHO cells (10⁹ cells) were suspended inphosphate-buffered saline supplemented with 5 mM EDTA (PBS-EDTA) andcentrifuged at 100×g for 5 minutes. To the cell pellet, 10 ml of a cellhomogenate buffer (10 mM NaHCO₃, 5 mM EDTA, pH 7.5) was added, followedby homogenization using the Polytron homogenizer. After centrifugationat 400×g for 15 minutes, the supernatant was transferred to anultracentrifugation tube and centrifuged at 100,000×g for 1 hour toyield a membrane fraction precipitate. This precipitate was suspended in2 ml of an assay buffer and centrifuged at 100,000×g for 1 hour. Themembrane fraction recovered as a precipitate was again suspended in 20ml of the assay buffer, dispensed, and stored at −80° C. before use uponthawing.

(4) Determination of ¹²⁵I-Leuprorelin Binding Inhibition Rate

The monkey and human membrane fractions prepared in the above (2) and(3) were diluted with the assay buffer to yield a 200 μg/ml dilution,each of which was then dispensed at 188 μl per tube. To a tubecontaining the cell membrane fraction of the CHO with monkey GnRHreceptors expressed were added 2 μl of a solution of 20 mM compound in60% DMSO and 10 μl of 38 nM ¹²⁵I-leuprorelin. To a tube containing thecell membrane fraction of the CHO with human GnRH receptors expressedwere added 2 μl of a solution of 2 mM compound in 60% DMSO and 10 μl of38 nM ¹²⁵I-leuprorelin. To determine maximum binding quantity, areaction mixture containing 2 μl of 60% DMSO and 10 μl of 38 nM¹²⁵I-leuprorelin was prepared. To determine non-specific binding amount,a reaction mixture containing 2 μl of a solution of 100 μM leuprorelinin 60% DMSO and 10 μl of 38 nM ¹²⁵I-leuprorelin was prepared.

Where the membrane fraction of the CHO with monkey and human GnRHreceptors expressed was used, the reaction was carried out at 25° C. for60 minutes. After each reaction, the reaction mixture was aspirated andfiltered through a polyethyleneimine-treated Whatman glass filter(GF-F). After this filtration, the radioactivity of 1251-leuprorelinremaining on the filter paper was measured with a γ-counter.

The expression (TB−SB)/(TB−NSB)×100 (where SB=radioactivity with thecompound added, TB=maximum bound radioactivity, NSB=nonspecificallybound radioactivity) was calculated to find the binding inhibition rateof each test compound. Furthermore, the inhibition rate was determinedby varying the concentration of the test substance and the 50%inhibitory concentration (IC₅₀ value) of the compound was calculatedfrom Hill plot. The results are shown in below. TABLE 1 IC₅₀ value (μM)Test Compound Monkey Human Ex. Compd. No. 40 0.009 0.0002 Ex. Compd. No.41 0.003 0.0001

INDUSTRIAL APPLICABILITY

The compound of the present invention possesses excellentgonadotropin-releasing hormone antagonizing activity. It is also good inoral absorbability and excellent in stability and pharmacokinetics. Withlow toxicity, it is also excellent in safety. Therefore, for example,the compound of the present invention can be used as a preventing ortreating agent for hormone-dependent diseases. Concretely, for example,it is effective as a preventing or treating agent for sexhormone-dependent cancers (e.g., prostatic cancer, uterine cancer,breast cancer, pituitary tumor, and the like), prostatic hypertrophy,hysteromyoma, endometriosis, metrofibroma, precocious puberty,amenorrhea syndrome, premenstrual syndrome, multilocular ovary syndrome,polycystic ovary syndrome, acne, alopecia, Alzheimer's disease, and thelike; as a pregnancy regulator (e.g., contraceptive, etc.), infertilityremedy or menstruation regulator, as a preventing or treating agent forirritable bowel syndrome; or as a preventing agent for postoperativerecurrence of sex hormone-dependent cancer, as medicament. It is alsoeffective as an animal estrous regulator, food meat quality improvingagent or animal growth regulator in the field of animal husbandry, andas a fish spawning promoter in the field of fishery.

1. A compound of the formula (I):

wherein R¹ is a C₁₋₄ alkyl; R² is (1) a C₁₋₆ alkyl which may have asubstituent selected from the group consisting of (1′) a hydroxy group,(2′) a C₁₋₄ alkoxy, (3′) a C₁₋₄ alkoxy-carbonyl, (4′) a di-C₁₋₄alkyl-carbamoyl, (5′) a 5- to 7-membered nitrogen-containingheterocyclic group, (6′) a C₁₋₄ alkyl-carbonyl and (7′) a halogen, (2) aC₃₋₈ cycloalkyl which may have (1′) a hydroxy group or (2′) a mono-C₁₋₄alkyl-carbonylamino, (3) a 5- to 7-membered nitrogen-containingheterocyclic group which may have a substituent selected from the groupconsisting of (1′) a halogen, (2′) a hydroxy group, (3′) a C₁₋₄ alkyland (4′) a C₁₋₄ alkoxy, (4) a phenyl which may have a substituentselected from the group consisting of (1′) a halogen, (2′) a C₁₋₄alkoxy-C₁₋₄ alkyl, (3′) a mono-C₁₋₄ alkyl-carbamoyl-C₁₋₄ alkyl, (4′) aC₁₋₄ alkoxy and (5′) a mono-C₁₋₄ alkyl-carbamoyl-C₁₋₄ alkoxy, or (5) aC₁₋₄ alkoxy; R³ is a C₁₋₄ alkyl; R⁴ is (1) a hydrogen atom, (2) a C₁₋₄alkoxy, (3) a C₆₋₁₀ aryl, (4) a N—C₁₋₄ alkyl-N—C₁₋₄ alkylsulfonylamino,(5) a hydroxyl group, or (6) a 5- to 7-membered nitrogen-containingheterocyclic group which may have a substituent selected from the groupconsisting of (1′) oxo, (2′) a C₁₋₄ alkyl, (3′) a hydroxy-C₁₋₄ alkyl,(4′) a C₁₋₄ alkoxy-carbonyl, (5′) a mono-C₁₋₄ alkyl-carbamoyl and (6′) aC₁₋₄ alkylsulfonyl; n is an integer of 1 to 4; provided that when R² isa phenyl which may have a substituent, R⁴ is a 5- to 7-memberednitrogen-containing heterocyclic group which may have a substituentselected from the group consisting of (1) oxo, (2) a hydroxy-C₁₋₄ alkyl,(3) a C₁₋₄ alkoxy-carbonyl, (4) a mono-C₁₋₄ alkyl-carbamoyl and (5) aC₁₋₄ alkylsulfonyl; or a salt thereof.
 2. A compound as claimed in claim1, wherein R² is (1) a C₁₋₄ alkyl which may have a substituent selectedfrom the group consisting of (1′) a hydroxy group, (2′) a C₁₋₄ alkoxy,(3′) a C₁₋₄ alkoxy-carbonyl, (4′) a di-C₁₋₄ alkyl-carbamoyl and (5′) a 5to 7-membered nitrogen-containing heterocyclic group, (2) a C₃₋₈cycloalkyl which may have (1′) a hydroxy group or (2′) a mono-C₁₋₄alkyl-carbonylamino, (3) a 5- to 7-membered nitrogen-containingheterocyclic group which may have a substituent selected from the groupconsisting of (1′) a halogen, (2′) a hydroxy group, (3′) a C₁₋₄ alkyland (4′) a C₁₋₄ alkoxy, (4) a phenyl which may have a substituentselected from the group consisting of (1′) a halogen, (2′) a C₁₋₄alkoxy-C₁₋₄ alkyl, (3′) a mono-C₁₋₄ alkyl-carbamoyl-C₁₋₄ alkyl and (4′)a mono-C₁₋₄ alkyl-carbamoyl-C₁₋₄ alkoxy, or (5) a C₁₋₄ alkoxy; R⁴ is (1)a C₁₋₄ alkoxy, (2) a C₆₋₁₀ aryl, (3) a N—C₁₋₄ alkyl-N—C₁₋₄alkylsulfonylamino or (4) a 5- to 7-membered nitrogen-containingheterocyclic group which may have a substituent selected from the groupconsisting of (1′) oxo, (2′) a hydroxy-C₁₋₄ alkyl, (3′) a C₁₋₄alkoxycarbonyl, (4′) a mono-C₁₋₄ alkyl-carbamoyl and (5′) a C₁₋₄alkylsulfonyl.
 3. A compound as claimed in claim 1, wherein R¹ ismethyl.
 4. A compound as claimed in claim 1, wherein R² is a 5- to7-membered nitrogen-containing heterocyclic group which may have asubstituent selected from the group consisting of (1) a halogen, (2) ahydroxy group, (3) a C₁₋₄ alkyl and (4) a C₁₋₄ alkoxy.
 5. A compound asclaimed in claim 1, wherein R³ is methyl.
 6. A compound as claimed inclaim 1, wherein R⁴ is a C₁₋₄ alkoxy.
 7. A compound as claimed in claim1, wherein n is
 2. 8. A compound as claimed in claim 1, wherein R³ ismethyl, R⁴ is a hydrogen atom and n is
 1. 9.N-(4-(1-(2,6-difluorobenzyl)-5(((2-methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-3-(2-pyridinyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxypyridin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a salt thereof. 10.N-(4-(5((2-methoxyethyl)methylamino)methyl)-1-(2,6-difluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxo-3-(4-methoxyphenyl)thieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyureaorN-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a salt thereof. 11-17. (canceled)
 18. A compound of the formula (A):

wherein R^(a) is (1) a hydrogen atom, (2) an aryl group which may have 1to 5 substituents selected from the group consisting of (i) a halogen,(ii) nitro, (iii) cyano, (iv) amino, (v) a carboxyl group which may beesterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) analkoxy, (ix) an alkylthio, (x) an alkylsulfinyl and (xi) analkylsulfonyl, (3) a cycloalkyl group which may have a substituent or(4) a heterocyclic group which may have a substituent; R^(b) is anitrogen-containing heterocyclic group which may have a substituent;R^(c) is an amino group which may have a substituent; R^(d) is an arylgroup which may have a substituent; p is an integer of 0 to 3; q is aninteger of 0 to 3; or a salt thereof. 19.N-(4-(1-(2,6-difluorobenzyl)-3-(4-(1-hydroxy-1-methylethyl)phenyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,N-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-3-(4-(1-hydroxy-1-methylethyl)phenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,N-(4-(1-(2,6-difluorobenzyl)-3((1-(hydroxymethyl)cyclopropyl)methyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-2,4-dioxo1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,or a salt thereof.
 20. A prodrug of the compound represented by formula(I)

wherein R¹ is a C₁₋₄ alkyl; R² is (1) a C₁₋₆ alkyl which may have asubstituent selected from the group consisting of (1′) a hydroxy group,(2′) a C₁₋₄ alkoxy, (3′) a C₁₋₄ alkoxy-carbonyl, (4′) a di-C₁₋₄alkyl-carbamoyl, (5′) a 5- to 7-membered nitrogen-containingheterocyclic group, (6′) a C₁₋₄ alkyl-carbonyl and (7′) a halogen, (2) aC₃₋₈ cycloalkyl which may have (1′) a hydroxy group or (2′) a mono-C₁₋₄alkyl-carbonylamino, (3) a 5- to 7-membered nitrogen-containingheterocyclic group which may have a substituent selected from the groupconsisting of (1′) a halogen, (2′) a hydroxy group, (3′) a C₁₋₄ alkyland (4′) a C₁₋₄ alkoxy, (4) a phenyl which may have a substituentselected from the group consisting of (1′) a halogen, (2′) a C₁₋₄alkoxy-C₁₋₄ alkyl, (3′) a mono-C₁₋₄ alkyl-carbamoyl-C₁₋₄ alkyl, (4′) aC₁₋₄ alkoxy and (5′) a mono-C₁₋₄ alkyl-carbamoyl-C₁₋₄ alkoxy, or (5) aC₁₋₄ alkoxy; R³ is a C₁₋₄ alkyl; R⁴ is (1) a hydrogen atom, (2) a C₁₋₄alkoxy, (3) a C₆₋₁₀ aryl, (4) a N—C₁₋₄ alkyl-N—C₁₋₄ alkylsulfonylamino,(5) a hydroxyl group, or (6) a 5- to 7-membered nitrogen-containingheterocyclic group which may have a substituent selected from the groupconsisting of (1′) oxo, (2′) a C₁₋₄ alkyl, (3′) a hydroxy-C₁₋₄ alkyl,(4′) a C₁₋₄ alkoxy-carbonyl, (5′) a mono-C₁₋₄ alkyl-carbamoyl and (6′) aC₁₋₄ alkylsulfonyl; n is an integer of 1 to 4; provided that when R² isa phenyl which may have a substituent, R⁴ is a 5- to 7-memberednitrogen-containing heterocyclic group which may have a substituentselected from the group consisting of (1) oxo, (2) a hydroxy-C₁₋₄ alkyl,(3) a C₁₋₄ alkoxy-carbonyl, (4) a mono-C₁₋₄ alkyl-carbamoyl and (5) aC₁₋₄ alkylsulfonyl; or a salt thereof.
 21. A pharmaceutical compositionwhich comprises the compound represented by formula (I):

wherein R¹ is a C₁₋₄ alkyl; R² is (1) a C₁₋₆ alkyl which may have asubstituent selected from the group consisting of (1′) a hydroxy group,(2′) a C₁₋₄ alkoxy, (3′) a C₁₋₄ alkoxy-carbonyl, (4′) a di-C₁₋₄alkyl-carbamoyl, (5′) a 5- to 7-membered nitrogen-containingheterocyclic group, (6′) a C₁₋₄ alkyl-carbonyl and (7′) a halogen, (2) aC₃₋₈ cycloalkyl which may have (1′) a hydroxy group or (2′) a mono-C₁₋₄alkyl-carbonylamino, (3) a 5- to 7-membered nitrogen-containingheterocyclic group which may have a substituent selected from the groupconsisting of (1′) a halogen, (2′) a hydroxy group, (3′) a C₁₋₄ alkyland (4′) a C₁₋₄ alkoxy, (4) a phenyl which may have a substituentselected from the group consisting of (1′) a halogen, (2′) a C₁₋₄alkoxy-C₁₋₄ alkyl, (3′) a mono-C₁₋₄ alkyl-carbamoyl-C₁₋₄ alkyl, (4′) aC₁₋₄ alkoxy and (5′) a mono-C₁₋₄ alkyl-carbamoyl-C₁₋₄ alkoxy, or (5) aC₁₋₄ alkoxy; R³ is a C₁₋₄ alkyl; R⁴ is (1) a hydrogen atom, (2) a C₁₋₄alkoxy, (3) a C₆₋₁₀ aryl, (4) a N—C₁₋₄ alkyl-N—C₁₋₄ alkylsulfonylamino,(5) a hydroxyl group, or (6) a 5- to 7-membered nitrogen-containingheterocyclic group which may have a substituent selected from the groupconsisting of (1′) oxo, (2′) a C₁₋₄ alkyl, (3′) a hydroxy-C₁₋₄ alkyl,(4′) a C₁₋₄ alkoxy-carbonyl, (5′) a mono-C₁₋₄ alkyl-carbamoyl and (6′) aC₁₋₄ alkylsulfonyl; n is an integer of 1 to 4; provided that when R² isa phenyl which may have a substituent, R⁴ is a 5- to 7-memberednitrogen-containing heterocyclic group which may have a substituentselected from the group consisting of (1) oxo, (2) a hydroxy-C₁₋₄ alkyl,(3) a C₁₋₄ alkoxy-carbonyl, (4) a mono-C₁₋₄ alkyl-carbamoyl and (5) aC₁₋₄ alkylsulfonyl; or a salt thereof or a prodrug thereof, and apharmacologically acceptable carrier, excipient or diluent.
 22. Apharmaceutical composition as claimed in claim 21, which is agonadotropin-releasing hormone antagonist.
 23. A pharmaceuticalcomposition as claimed in claim 21, which is for preventing or treatinga sex hormone dependent disease.
 24. A pharmaceutical composition asclaimed in claim 21, which is for preventing or treating sexhormone-dependent cancer, bone metastasis of sex hormone-dependentcancer, prostatic hypertrophy, hysteromyoma, endometriosis,metrofibroma, precocious puberty, amenorrhea, premenstrual syndrome,dysmenorrhea, multilocular ovary syndrome, polycystic ovary syndrome,acne, alopecia, Alzheimer's disease, infertility, irritable bowelsyndrome, benign or malignant tumor which is hormone independent andLH-RH sensitive or hot flash; reproduction regulator; contraceptiveagent; ovulation inducer; or for prevention of postoperative recurrenceof sex hormone-dependent cancer.
 25. A method for antagonizinggonadotropin-releasing hormone, which comprises administering aneffective amount of the compound represented by formula (I):

wherein R¹ is a C₁₋₄ alkyl; R² is (1) a C₁₋₆ alkyl which may have asubstituent selected from the group consisting of (1′) a hydroxy group,(2′) a C₁₋₄ alkoxy, (3′) a C₁₋₄ alkoxy-carbonyl, (4′) a di-C₁₋₄alkyl-carbamoyl, (5′) a 5- to 7-membered nitrogen-containingheterocyclic group, (6′) a C₁₋₄ alkyl-carbonyl and (7′) a halogen, (2) aC₃₋₈ cycloalkyl which may have (1′) a hydroxy group or (2′) a mono-C₁₋₄alkyl-carbonylamino, (3) a 5- to 7-membered nitrogen-containingheterocyclic group which may have a substituent selected from the groupconsisting of (1′) a halogen, (2′) a hydroxy group, (3′) a C₁₋₄ alkyland (4′) a C₁₋₄ alkoxy, (4) a phenyl which may have a substituentselected from the group consisting of (1′) a halogen, (2′) a C₁₋₄alkoxy-C₁₋₄ alkyl, (3′) a mono-C₁₋₄ alkyl-carbamoyl-C₁₋₄ alkyl, (4′) aC₁₋₄ alkoxy and (5′) a mono-C₁₋₄ alkyl-carbamoyl-C₁₋₄ alkoxy, or (5) aC₁₋₄ alkoxy; R³ is a C₁₋₄ alkyl; R⁴ is (1) a hydrogen atom, (2) a C₁₋₄alkoxy, (3) a C₆₋₁₀ aryl, (4) a N—C₁₋₄ alkyl-N—C₁₋₄ alkylsulfonylamino,(5) a hydroxyl group, or (6) a 5- to 7-membered nitrogen-containingheterocyclic group which may have a substituent selected from the groupconsisting of (1′) oxo, (2′) a C₁₋₄ alkyl, (3′) a hydroxy-C₁₋₄ alkyl,(4′) a C₁₋₄ alkoxy-carbonyl, (5′) a mono-C₁₋₄ alkyl-carbamoyl and (6′) aC₁₋₄ alkylsulfonyl; n is an integer of 1 to 4; provided that when R² isa phenyl which may have a substituent, R⁴ is a 5- to 7-memberednitrogen-containing heterocyclic group which may have a substituentselected from the group consisting of (1) oxo, (2) a hydroxy-C₁₋₄ alkyl,(3) a C₁₋₄ alkoxy-carbonyl, (4) a mono-C₁₋₄ alkyl-carbamoyl and (5) aC₁₋₄ alkylsulfonyl; or a salt thereof to a mammal.
 26. A method formanufacturing a pharmaceutical composition for antagonizinggonadotropin-releasing hormone which comprises mixing the compoundrepresented by formula (I):

wherein R¹ is a C₁₋₄ alkyl; R² is (1) a C₁₋₆ alkyl which may have asubstituent selected from the group consisting of (1′) a hydroxy group,(2′) a C₁₋₄ alkoxy, (3′) a C₁₋₄ alkoxy-carbonyl, (4′) a di-C₁₋₄alkyl-carbamoyl, (5′) a 5- to 7-membered nitrogen-containingheterocyclic group, (6′) a C₁₋₄ alkyl-carbonyl and (7′) a halogen, (2) aC₃₋₈ cycloalkyl which may have (1′) a hydroxy group or (2′) a mono-C₁₋₄alkyl-carbonylamino, (3) a 5- to 7-membered nitrogen-containingheterocyclic group which may have a substituent selected from the groupconsisting of (1′) a halogen, (2′) a hydroxy group, (3′) a C₁₋₄ alkyland (4′) a C₁₋₄ alkoxy, (4) a phenyl which may have a substituentselected from the group consisting of (1′) a halogen, (2′) a C₁₋₄alkoxy-C₁₋₄ alkyl, (3′) a mono-C₁₋₄ alkyl-carbamoyl-C₁₋₄ alkyl, (4′) aC₁₋₄ alkoxy and (5′) a mono-C₁₋₄ alkyl-carbamoyl-C₁₋₄ alkoxy, or (5) aC₁₋₄ alkoxy; R³ is a C₁₋₄ alkyl; R⁴ is (1) a hydrogen atom, (2) a C₁₋₄alkoxy, (3) a C₆₋₁₀ aryl, (4) a N—C₁₋₄ alkyl-N—C₁₋₄ alkylsulfonylamino,(5) a hydroxyl group, or (6) a 5- to 7-membered nitrogen-containingheterocyclic group which may have a substituent selected from the groupconsisting of (1′) oxo, (2′) a C₁₋₄ alkyl, (3′) a hydroxy-C₁₋₄ alkyl,(4′) a C₁₋₄ alkoxy-carbonyl, (5′) a mono-C₁₋₄ alkyl-carbamoyl and (6′) aC₁₋₄ alkylsulfonyl; n is an integer of 1 to 4; provided that when R² isa phenyl which may have a substituent, R⁴ is a 5- to 7-memberednitrogen-containing heterocyclic group which may have a substituentselected from the group consisting of (1) oxo, (2) a hydroxy-C₁₋₄ alkyl,(3) a C₁₋₄ alkoxy-carbonyl, (4) a mono-C₁₋₄ alkyl-carbamoyl and (5) aC₁₋₄ alkylsulfonyl; or a salt thereof; and a pharmacologicallyacceptable carrier, excipient or diluent.
 27. A method for preventingand/or treating diseases selected from the group consisting ofsex-hormone dependent cancers, bone metastasis of the sexhormone-dependent cancers, prostatic hypertrophy, hysteromyoma,endometriosis, metrofibroma, precocious puberty, amenorrhea,premenstrual syndrome, dysmenorrhea, multilocular ovary syndrome,polycystic ovary syndrome, acne, alopecia, Alzheimer's disease,infertility, irritable bowel syndrome and LH-RH sensitive benign ormalignant tumor which is independent of the hormone; for regulatingreproduction, contraception or induction of ovulation; or for preventingpostoperative recurrence of sex hormone-dependent cancers, byantagonizing gonadotropin-releasing hormone, which comprisesadministering an effective amount of the compound represented by formula(I):

wherein R¹ is a C₁₋₄ alkyl; R² is (1) a C₁₋₆ alkyl which may have asubstituent selected from the group consisting of (1′) a hydroxy group,(2′) a C₁₋₄ alkoxy, (3′) a C₁₋₄ alkoxy-carbonyl, (4′) a di-C₁₋₄alkyl-carbamoyl, (5′) a 5- to 7-membered nitrogen-containingheterocyclic group, (6′) a C₁₋₄ alkyl-carbonyl and (7′) a halogen, (2) aC₃₋₈ cycloalkyl which may have (1′) a hydroxy group or (2′) a mono-C₁₋₄alkyl-carbonylamino, (3) a 5- to 7-membered nitrogen-containingheterocyclic group which may have a substituent selected from the groupconsisting of (1′) a halogen, (2′) a hydroxy group, (3′) a C₁₋₄ alkyland (4′) a C₁₋₄ alkoxy, (4) a phenyl which may have a substituentselected from the group consisting of (1′) a halogen, (2′) a C₁₋₄alkoxy-C₁₋₄ alkyl, (3′) a mono-C₁₋₄ alkyl-carbamoyl-C₁₋₄ alkyl, (4′) aC₁₋₄ alkoxy and (5′) a mono-C₁₋₄ alkyl-carbamoyl-C₁₋₄ alkoxy, or (5) aC₁₋₄ alkoxy; R³ is a C₁₋₄ alkyl; R⁴ is (1) a hydrogen atom, (2) a C₁₋₄alkoxy, (3) a C₆₋₁₀ aryl, (4) a N—C₁₋₄ alkyl-N—C₁₋₄ alkylsulfonylamino,(5) a hydroxyl group, or (6) a 5- to 7-membered nitrogen-containingheterocyclic group which may have a substituent selected from the groupconsisting of (1′) oxo, (2′) a C₁₋₄ alkyl, (3′) a hydroxy-C₁₋₄ alkyl,(4′) a C₁₋₄ alkoxy-carbonyl, (5′) a mono-C₁₋₄ alkyl-carbamoyl and (6′) aC₁₋₄ alkylsulfonyl; n is an integer of 1 to 4; provided that when R² isa phenyl which may have a substituent, R⁴ is a 5- to 7-memberednitrogen-containing heterocyclic group which may have a substituentselected from the group consisting of (1) oxo, (2) a hydroxy-C₁₋₄ alkyl,(3) a C₁₋₄ alkoxy-carbonyl, (4) a mono-C₁₋₄ alkyl-carbamoyl and (5) aC₁₋₄ alkylsulfonyl; or a salt thereof; to a mammal.
 28. A method forpreventing and/or treating diseases depending on male or female hormone,diseases due to excess of these hormones, by suppressing gonadotropinsecretion with its gonadotropin-releasing hormone receptor-antagonizingaction to control plasma sex hormone concentrations, which comprisesadministering an effective amount of the compound represented by formula(I):

wherein R¹ is a C₁₋₄ alkyl; R² is (1) a C₁₋₆ alkyl which may have asubstituent selected from the group consisting of (1′) a hydroxy group,(2′) a C₁₋₄ alkoxy, (3′) a C₁₋₄ alkoxy-carbonyl, (4′) a di-C₁₋₄alkyl-carbamoyl, (5′) a 5- to 7-membered nitrogen-containingheterocyclic group, (6′) a C₁₋₄ alkyl-carbonyl and (7′) a halogen, (2) aC₃₋₈cycloallyl which may have (1′) a hydroxy group or (2′) a mono-C₁₋₄alkyl-carbonylamino, (3) a 5- to 7-membered nitrogen-containingheterocyclic group which may have a substituent selected from the groupconsisting of (1′) a halogen, (2′) a hydroxy group, (3′) a C₁₋₄ alkyland (4′) a C₁₋₄ alkoxy, (4) a phenyl which may have a substituentselected from the group consisting of (1′) a halogen, (2′) a C₁₋₄alkoxy-C₁₋₄ alkyl, (3′) a mono-C₁₋₄ alkyl-carbamoyl-C₁₋₄ alkyl, (4′) aC₁₋₄ alkoxy and (5′) a mono-C₁₋₄ alkyl-carbamoyl-C₁₋₄ alkoxy, or (5) aC₁₋₄ alkoxy; R³ is a C₁₋₄ alkyl; R⁴ is (1) a hydrogen atom, (2) a C₁₋₄alkoxy, (3) a C₆₋₁₀ aryl, (4) a N—C₁₋₄ alkyl-N—C₁₋₄ alkylsulfonylamino,(5) a hydroxyl group, or (6) a 5- to 7-membered nitrogen-containingheterocyclic group which may have a substituent selected from the groupconsisting of (1′) oxo, (2′) a C₁₋₄ alkyl, (3′) a hydroxy-C₁₋₄ alkyl,(4′) a C₁₋₄ alkoxy-carbonyl, (5′) a mono-C₁₋₄ alkyl-carbamoyl and (6′) aC₁₋₄ alkylsulfonyl; n is an integer of 1 to 4; provided that when R² isa phenyl which may have a substituent, R⁴ is a 5- to 7-memberednitrogen-containing heterocyclic group which may have a substituentselected from the group consisting of (1) oxo, (2) a hydroxy-C₁₋₄ alkyl,(3) a C₁₋₄ alkoxy-carbonyl, (4) a mono-C₁₋₄ alkyl-carbamoyl and (5) aC₁₋₄ alkylsulfonyl; or a salt thereof; to a mammal.
 29. A method forpreventing and/or treating diseases depending on sex hormone, LH-RHsensitive benign or malignant tumor which is independent of the hormoneor irritable bowel syndrome; for regulating reproduction in male orfemales, male or female contraception, induction of ovulation, or animalestrus; for preventing postoperative recurrence of sex hormone-dependentcancers; for improving meat quality; or for promoting animal growth orfish spawning, which comprises administering an effective amount of thecompound represented by formula (I):

wherein R¹ is a C₁₋₄ alkyl; R² is (1) a C₁₋₆ alkyl which may have asubstituent selected from the group consisting of (1′) a hydroxy group,(2′) a C₁₋₄ alkoxy, (3′) a C₁₋₄ alkoxy-carbonyl, (4′) a di-C₁₋₄alkyl-carbamoyl, (5′) a 5- to 7-membered nitrogen-containingheterocyclic group, (6′) a C₁₋₄ alkyl-carbonyl and (7′) a halogen, (2) aC₃₋₈ cycloalkyl which may have (1′) a hydroxy group or (2′) a mono-C₁₋₄alkyl-carbonylamino, (3) a 5- to 7-membered nitrogen-containingheterocyclic group which may have a substituent selected from the groupconsisting of (1′) a halogen, (2′) a hydroxy group, (3′) a C₁₋₄ alkyland (4′) a C₁₋₄ alkoxy, (4) a phenyl which may have a substituentselected from the group consisting of (1′) a halogen, (2′) a C₁₋₄alkoxy-C₁₋₄ alkyl, (3′) a mono-C₁₋₄ alkyl-carbamoyl-C₁₋₄ alkyl, (4′) aC₁₋₄ alkoxy and (5′) a mono-C₁₋₄ alkyl-carbamoyl-C₁₋₄ alkoxy, or (5) aC₁₋₄ alkoxy; R³ is a C₁₋₄ alkyl; R⁴ is (1) a hydrogen atom, (2) a C₁₋₄alkoxy, (3) a C₆₋₁₀ aryl, (4) a N—C₁₋₄ alkyl-N—C₁₋₄ alkylsulfonylamino,(5) a hydroxyl group, or (6) a 5- to 7-membered nitrogen-containingheterocyclic group which may have a substituent selected from the groupconsisting of (1′) oxo, (2′) a C₁₋₄ alkyl, (3′) a hydroxy-C₁₋₄ alkyl,(4′) a C₁₋₄ alkoxy-carbonyl, (5′) a mono-C₁₋₄ alkyl-carbamoyl and (6′) aC₁₋₄ alkylsulfonyl; n is an integer of 1 to 4; provided that when R² isa phenyl which may have a substituent, R⁴ is a 5- to 7-memberednitrogen-containing heterocyclic group which may have a substituentselected from the group consisting of (1) oxo, (2) a hydroxy-C₁₋₄ alkyl,(3) a C₁₋₄ alkoxy-carbonyl, (4) a mono-C₁₋₄ alkyl-carbamoyl and (5) aC₁₋₄ alkylsulfonyl; or a salt thereof; to a mammal.
 30. A prodrug of thecompound represented by formula (A):

wherein R^(a) is (1) a hydrogen atom, (2) an aryl group which may have 1to 5 substituents selected from the group consisting of (i) a halogen,(ii) nitro, (iii) cyano, (iv) amino, (v) a carboxyl group which may beesterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) analkoxy, (ix) an alkylthio, (x) an alkylsulfinyl and (xi) analkylsulfonyl, (3) a cycloalkyl group which may have a substituent or(4) a heterocyclic group which may have a substituent; R^(b) is anitrogen-containing heterocyclic group which may have a substituent;R^(c) is an amino group which may have a substituent; R^(d) is an arylgroup which may have a substituent; p is an integer of 0 to 3; q is aninteger of 0 to 3; or a salt thereof.
 31. A pharmaceutical compositionwhich comprises the compound represented by formula (A):

wherein R^(a) is (1) a hydrogen atom, (2) an aryl group which may have 1to 5 substituents selected from the group consisting of (i) a halogen,(ii) nitro, (iii) cyano, (iv) amino, (v) a carboxyl group which may beesterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) analkoxy, (ix) an alkylthio, (x) an alkylsulfinyl and (xi) analkylsulfonyl, (3) a cycloalkyl group which may have a substituent or(4) a heterocyclic group which may have a substituent; R^(b) is anitrogen-containing heterocyclic group which may have a substituent;R^(c) is an amino group which may have a substituent; R^(d) is an arylgroup which may have a substituent; p is an integer of 0 to 3; q is aninteger of 0 to 3; or a salt thereof or a prodrug thereof, and apharmacologically acceptable carrier, excipient or diluent.
 32. Apharmaceutical composition as claimed in claim 31, which is agonadotropin-releasing hormone antagonist.
 33. A pharmaceuticalcomposition as claimed in claim 31, which is for preventing or treatinga sex hormone dependent disease.
 34. A pharmaceutical composition asclaimed in claim 31, which is for preventing or treating sexhormone-dependent cancer, bone metastasis of sex hormone-dependentcancer, prostatic hypertrophy, hysteromyoma, endometriosis,metrofibroma, precocious puberty, amenorrhea, premenstrual syndrome,dysmenorrhea, multilocular ovary syndrome, polycystic ovary syndrome,acne, alopecia, Alzheimer's disease, infertility, irritable bowelsyndrome, benign or malignant tumor which is hormone independent andLH-RH sensitive or hot flash; reproduction regulator; contraceptiveagent; ovulation inducer; or for prevention of postoperative recurrenceof sex hormone-dependent cancer.
 35. A method for antagonizinggonadotropin-releasing hormone, which comprises administering aneffective amount of the compound represented by formula (A):

wherein R^(a) is (1) a hydrogen atom, (2) an aryl group which may have 1to 5 substituents selected from the group consisting of (i) a halogen,(ii) nitro, (iii) cyano, (iv) amino, (v) a carboxyl group which may beesterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) analkoxy, (ix) an alkylthio, (x) an alkylsulfonyl and (xi) analkylsulfonyl, (3) a cycloalkyl group which may have a substituent or(4) a heterocyclic group which may have a substituent; R^(b) is anitrogen-containing heterocyclic group which may have a substituent;R^(c) is an amino group which may have a substituent; R^(d) is an arylgroup which may have a substituent; p is an integer of 0 to 3; q is aninteger of 0 to 3; or a salt thereof to a mammal.
 36. A method formanufacturing a pharmaceutical composition for antagonizinggonadotropin-releasing hormone which comprises mixing the compoundrepresented by formula (A)

wherein R^(a) is (1) a hydrogen atom, (2) an aryl group which may have 1to 5 substituents selected from the group consisting of (i) a halogen,(ii) nitro, (iii) cyano, (iv) amino, (v) a carboxyl group which may beesterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) analkoxy, (ix) an alkylthio, (x) an alkylsulfinyl and (xi) analkylsulfonyl, (3) a cycloalkyl group which may have a substituent or(4) a heterocyclic group which may have a substituent; R^(b) is anitrogen-containing heterocyclic group which may have a substituent;R^(c) is an amino group which may have a substituent; R^(d) is an arylgroup which may have a substituent; p is an integer of 0 to 3; q is aninteger of 0 to 3; or a salt thereof; and a pharmacologically acceptablecarrier, excipient or diluent.
 37. A method for preventing and/ortreating diseases selected from the group consisting of sex-hormonedependent cancers, bone metastasis of the sex hormone-dependent cancers,prostatic hypertrophy, hysteromyoma, endometriosis, metrofibroma,precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea,multilocular ovary syndrome, polycystic ovary syndrome, acne, alopecia,Alzheimer's disease, infertility, irritable bowel syndrome and LH-RHsensitive benign or malignant tumor which is independent of the hormone;for regulating reproduction, contraception or induction of ovulation; orfor preventing postoperative recurrence of sex hormone-dependentcancers, by antagonizing gonadotropin-releasing hormone, which comprisesadministering an effective amount of the compound represented by formula(A):

wherein R^(a) is (1) a hydrogen atom, (2) an aryl group which may have 1to 5 substituents selected from the group consisting of (i) a halogen,(ii) nitro, (iii) cyano, (iv) amino, (v) a carboxyl group which may beesterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) analkoxy, (ix) an alkylthio, (x) an alkylsulfinyl and (xi) analkylsulfonyl, (3) a cycloalkyl group which may have a substituent or(4) a heterocyclic group which may have a substituent; R^(b) is anitrogen-containing heterocyclic group which may have a substituent;R^(c) is an amino group which may have a substituent; R^(d) is an arylgroup which may have a substituent; p is an integer of 0 to 3; q is aninteger of 0 to 3; or a salt thereof; to a mammal.
 38. A method forpreventing and/or treating diseases depending on male or female hormone,diseases due to excess of these hormones, by suppressing gonadotropinsecretion with its gonadotropin-releasing hormone receptor-antagonizingaction to control plasma sex hormone concentrations, which comprisesadministering an effective amount of the compound represented by formula(A):

wherein R^(a) is (1) a hydrogen atom, (2) an aryl group which may have 1to 5 substituents selected from the group consisting of (i) a halogen,(ii) nitro, (iii) cyano, (iv) amino, (v) a carboxyl group which may beesterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) analkoxy, (ix) an alkylthio, (x) an alkylsulfinyl and (xi) analkylsulfonyl, (3) a cycloalkyl group which may have a substituent or(4) a heterocyclic group which may have a substituent; R^(b) is anitrogen-containing heterocyclic group which may have a substituent;R^(c) is an amino group which may have a substituent; R^(d) is an arylgroup which may have a substituent; p is an integer of 0 to 3; q is aninteger of 0 to 3; or a salt thereof; to a mammal.
 39. A method forpreventing and/or treating diseases depending on sex hormone, LH-RHsensitive benign or malignant tumor which is independent of the hormoneor irritable bowel syndrome; for regulating reproduction in male orfemales, male or female contraception, induction of ovulation, or animalestrus; for preventing postoperative recurrence of sex hormone-dependentcancers; for improving meat quality; or for promoting animal growth orfish spawning, which comprises administering an effective amount of thecompound represented by formula (A):

wherein R^(a) is (1) a hydrogen atom, (2) an aryl group which may have 1to 5 substituents selected from the group consisting of (i) a halogen,(ii) nitro, (iii) cyano, (iv) amino, (v) a carboxyl group which may beesterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) analkoxy, (ix) an alkylthio, (x) an alkylsulfinyl and (xi) analkylsulfonyl, (3) a cycloalkyl group which may have a substituent or(4) a heterocyclic group which may have a substituent; R^(b) is anitrogen-containing heterocyclic group which may have a substituent;R^(c) is an amino group which may have a substituent; R^(d) is an arylgroup which may have a substituent; p is an integer of 0 to 3; q is aninteger of 0 to 3; or a salt thereof; to a mammal.